Immunology and Microbiology › Immunology

Immune Response and Inflammation

Works Count: 85472

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Description

This cluster of papers focuses on the recognition and signaling pathways of innate immunity, particularly through Toll-like receptors and pattern recognition receptors. It explores the role of these receptors in pathogen recognition, inflammation, antiviral responses, and the regulation of adaptive immunity. The cluster also delves into the molecular mechanisms and mediators involved in innate immune responses.

Keywords

Toll-like Receptors; Pattern Recognition Receptors; Inflammation; Innate Antiviral Responses; Cytokine-Mediated Link; Pathogen Recognition; NOD-Like Receptors; Endotoxin Hyporesponsiveness; DAMPs; Adaptive Immunity Regulation

A Toll-like receptor recognizes bacterial DNA

2000-12-07

Hiroaki Hemmi , Osamu Takeuchi , Taro Kawai +7 more

The innate immune response to bacterial flagellin is mediated by Toll-like receptor 5

2001-04-01

Fumitaka Hayashi , Kelly D. Smith , Adrian Ozinsky +7 more

Immunosuppression by Glucocorticoids: Inhibition of NF-κB Activity Through Induction of IκB Synthesis

1995-10-13

Nathalie Auphan‐Anezin , Joseph A. DiDonato , Caridad Rosette +2 more

Glucocorticoids are among the most potent anti-inflammatory and immunosuppressive agents. They inhibit synthesis of almost all known cytokines and of several cell surface molecules required for immune function, but the … Glucocorticoids are among the most potent anti-inflammatory and immunosuppressive agents. They inhibit synthesis of almost all known cytokines and of several cell surface molecules required for immune function, but the mechanism underlying this activity has been unclear. Here it is shown that glucocorticoids are potent inhibitors of nuclear factor kappa B (NF-κB) activation in mice and cultured cells. This inhibition is mediated by induction of the IκBα inhibitory protein, which traps activated NF-κB in inactive cytoplasmic complexes. Because NF-κB activates many immunoregulatory genes in response to pro-inflammatory stimuli, the inhibition of its activity can be a major component of the anti-inflammatory activity of glucocorticoids.

Reactive oxygen intermediates as apparently widely used messengers in the activation of the NF-kappa B transcription factor and HIV-1.

1991-08-01

Ralf Schreck , P. Rieber , Patrick A. Baeuerle

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Association of NOD2 leucine-rich repeat variants with susceptibility to Crohn's disease

2001-05-01

Jean‐Pierre Hugot , Mathias Chamaillard , Habib Zouali +7 more

Toll-like receptors: critical proteins linking innate and acquired immunity

2001-08-01

Shizuo Akira , Kiyoshi Takeda , Tsuneyasu Kaisho

Interleukin-6 and the acute phase response

1990-02-01

Peter C. Heinrich , José V. Castell , Tilo Andus

Research Article| February 01 1990 Interleukin-6 and the acute phase response P C Heinrich; P C Heinrich *Institut für Biochemie der RWTH Aachen, Pauwelsstraße, 5100 Aachen, Federal Republic of Germany. … Research Article| February 01 1990 Interleukin-6 and the acute phase response P C Heinrich; P C Heinrich *Institut für Biochemie der RWTH Aachen, Pauwelsstraße, 5100 Aachen, Federal Republic of Germany. Search for other works by this author on: This Site PubMed Google Scholar J V Castell; J V Castell †Unidad de Hepatologia Experimental, Centro de Investigación, Hospital La Fe, Avenida de Campanar 21, 46009 Valencia, Spain Search for other works by this author on: This Site PubMed Google Scholar T Andus T Andus ‡Medizinische Universitätsklinik Freiburg, Hugstetter Straße 55, 7800 Freiburg, Federal Republic of Germany Search for other works by this author on: This Site PubMed Google Scholar Author and article information Publisher: Portland Press Ltd Online ISSN: 1470-8728 Print ISSN: 0264-6021 © 1990 London: The Biochemical Society1990 Biochem J (1990) 265 (3): 621–636. https://doi.org/10.1042/bj2650621 Views Icon Views Article contents Figures & tables Video Audio Supplementary Data Peer Review Share Icon Share Facebook Twitter LinkedIn Email Cite Icon Cite Get Permissions Citation P C Heinrich, J V Castell, T Andus; Interleukin-6 and the acute phase response. Biochem J 1 February 1990; 265 (3): 621–636. doi: https://doi.org/10.1042/bj2650621 Download citation file: Ris (Zotero) Reference Manager EasyBib Bookends Mendeley Papers EndNote RefWorks BibTex toolbar search Search Dropdown Menu toolbar search search input Search input auto suggest filter your search All ContentAll JournalsBiochemical Journal Search Advanced Search This content is only available as a PDF. © 1990 London: The Biochemical Society1990 Article PDF first page preview Close Modal You do not currently have access to this content.

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Toll-like receptors in the induction of the innate immune response

2000-08-17

Alan Aderem , Richard J. Ulevitch

Shock and Tissue Injury Induced by Recombinant Human Cachectin

1986-10-24

Kevin J. Tracey , Bruce Beutler , Stephen F. Lowry +7 more

Cachectin (tumor necrosis factor), a protein produced in large quantities by endotoxin-activated macrophages, has been implicated as an important mediator of the lethal effect of endotoxin. Recombinant human cachectin was … Cachectin (tumor necrosis factor), a protein produced in large quantities by endotoxin-activated macrophages, has been implicated as an important mediator of the lethal effect of endotoxin. Recombinant human cachectin was infused into rats in an effort to determine whether cachectin, by itself, can elicit the derangements of host physiology caused by administration of endotoxin. When administered in quantities similar to those produced endogenously in response to endotoxin, cachectin causes hypotension, metabolic acidosis, hemoconcentration, and death within minutes to hours, as a result of respiratory arrest. Hyperglycemia and hyperkalemia were also observed after infusion. At necropsy, diffuse pulmonary inflammation and hemorrhage were apparent on gross and histopathologic examination, along with ischemic and hemorrhagic lesions of the gastrointestinal tract, and acute renal tubular necrosis. Thus, it appears that a single protein mediator (cachectin) is capable of inducing many of the deleterious effects of endotoxin.

Species-Specific Recognition of Single-Stranded RNA via Toll-like Receptor 7 and 8

2004-02-24

Florian Heil , Hiroaki Hemmi , Hubertus Hochrein +6 more

Double-stranded ribonucleic acid (dsRNA) serves as a danger signal associated with viral infection and leads to stimulation of innate immune cells. In contrast, the immunostimulatory potential of single-stranded RNA (ssRNA) … Double-stranded ribonucleic acid (dsRNA) serves as a danger signal associated with viral infection and leads to stimulation of innate immune cells. In contrast, the immunostimulatory potential of single-stranded RNA (ssRNA) is poorly understood and innate immune receptors for ssRNA are unknown. We report that guanosine (G)- and uridine (U)-rich ssRNA oligonucleotides derived from human immunodeficiency virus–1 (HIV-1) stimulate dendritic cells (DC) and macrophages to secrete interferon-α and proinflammatory, as well as regulatory, cytokines. By using Toll-like receptor (TLR)–deficient mice and genetic complementation, we show that murine TLR7 and human TLR8 mediate species-specific recognition of GU-rich ssRNA. These data suggest that ssRNA represents a physiological ligand for TLR7 and TLR8.

Small anti-viral compounds activate immune cells via the TLR7 MyD88–dependent signaling pathway

2002-01-22

Hiroaki Hemmi , Tsuneyasu Kaisho , Osamu Takeuchi +7 more

Cutting Edge: Toll-Like Receptor 4 (TLR4)-Deficient Mice Are Hyporesponsive to Lipopolysaccharide: Evidence for TLR4 as the Lps Gene Product

1999-04-01

Katsuaki Hoshino , Osamu Takeuchi , Taro Kawai +5 more

Abstract The human homologue of Drosophila Toll (hToll), also called Toll-like receptor 4 (TLR4), is a recently cloned receptor of the IL-1/Toll receptor family. Interestingly, the TLR4 gene has been … Abstract The human homologue of Drosophila Toll (hToll), also called Toll-like receptor 4 (TLR4), is a recently cloned receptor of the IL-1/Toll receptor family. Interestingly, the TLR4 gene has been localized to the same region to which the Lps locus (endotoxin unresponsive gene locus) is mapped. To examine the role of TLR4 in LPS responsiveness, we have generated mice lacking TLR4. Macrophages and B cells from TLR4-deficient mice did not respond to LPS. All these manifestations were quite similar to those of LPS-hyporesponsive C3H/HeJ mice. Furthermore, C3H/HeJ mice have, in the cytoplasmic portion of TLR4, a single point mutation of the amino acid that is highly conserved among the IL-1/Toll receptor family. Overexpression of wild-type TLR4 but not the mutant TLR4 from C3H/HeJ mice activated NF-κB. Taken together, the present study demonstrates that TLR4 is the gene product that regulates LPS response.

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Bidirectional cytokine interactions in the maternal-fetal relationship: is successful pregnancy a TH2 phenomenon?

1993-07-01

Thomas Wegmann , Hui Lin , Larry J. Guilbert +1 more

A sensitive silver stain for detecting lipopolysaccharides in polyacrylamide gels

1982-01-01

Chao-Ming Tsai , Carl E. Frasch

Innate Antiviral Responses by Means of TLR7-Mediated Recognition of Single-Stranded RNA

2004-02-24

Sandra S. Diebold , Tsuneyasu Kaisho , Hiroaki Hemmi +2 more

Interferons (IFNs) are critical for protection from viral infection, but the pathways linking virus recognition to IFN induction remain poorly understood. Plasmacytoid dendritic cells produce vast amounts of IFN-α in … Interferons (IFNs) are critical for protection from viral infection, but the pathways linking virus recognition to IFN induction remain poorly understood. Plasmacytoid dendritic cells produce vast amounts of IFN-α in response to the wild-type influenza virus. Here, we show that this requires endosomal recognition of influenza genomic RNA and signaling by means of Toll-like receptor 7 (TLR7) and MyD88. Single-stranded RNA (ssRNA) molecules of nonviral origin also induce TLR7-dependent production of inflammatory cytokines. These results identify ssRNA as a ligand for TLR7 and suggest that cells of the innate immune system sense endosomal ssRNA to detect infection by RNA viruses.

Toll-like Receptors and Their Crosstalk with Other Innate Receptors in Infection and Immunity

2011-05-01

Taro Kawai , Shizuo Akira

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Pathogen Recognition and Innate Immunity

2006-02-01

Shizuo Akira , Satoshi Uematsu , Osamu Takeuchi

Passive Immunization Against Cachectin/Tumor Necrosis Factor Protects Mice from Lethal Effect of Endotoxin

1985-08-30

Bruce Beutler , Ian W. Milsark , Anthony Cerami

A highly specific polyclonal rabbit antiserum directed against murine cachectin/tumor necrosis factor (TNF) was prepared. When BALB/c mice were passively immunized with the antiserum or with purified immune globulin, they … A highly specific polyclonal rabbit antiserum directed against murine cachectin/tumor necrosis factor (TNF) was prepared. When BALB/c mice were passively immunized with the antiserum or with purified immune globulin, they were protected against the lethal effect of the endotoxin lipopolysaccharide produced by Escherichia coli . The prophylactic effect was dose-dependent and was most effective when the antiserum was administered prior to the injection of the endotoxin. Antiserum to cachectin/TNF did not mitigate the febrile response of endotoxin-treated animals, and very high doses of endotoxin could overcome the protective effect. The median lethal dose of endotoxin in mice pretreated with 50 microliters of the specific antiserum was approximately 2.5 times greater the median lethal dose for controls given nonimmune serum. The data suggest that cachectin/TNF is one of the principal mediators of the lethal effect of endotoxin.

Toll-like receptor signalling

2004-06-30

Shizuo Akira , Kiyoshi Takeda

Toll-like receptors and innate immunity

2001-11-01

Ruslan Medzhitov

CD14, a Receptor for Complexes of Lipopolysaccharide (LPS) and LPS Binding Protein

1990-09-21

Samuel D. Wright , Robert Ramos , Peter S. Tobias +2 more

Leukocytes respond to lipopolysaccharide (LPS) at nanogram per milliliter concentrations with secretion of cytokines such as tumor necrosis factor-α (TNF-α). Excess secretion of TNF-α causes endotoxic shock, an often fatal … Leukocytes respond to lipopolysaccharide (LPS) at nanogram per milliliter concentrations with secretion of cytokines such as tumor necrosis factor-α (TNF-α). Excess secretion of TNF-α causes endotoxic shock, an often fatal complication of infection. LPS in the bloodstream rapidly binds to the serum protein, lipopolysaccharide binding protein (LBP), and cellular responses to physiological levels of LPS are dependent on LBP. CD14, a differentiation antigen of monocytes, was found to bind complexes of LPS and LBP, and blockade of CD14 with monoclonal antibodies prevented synthesis of TNF-α by whole blood incubated with LPS. Thus, LPS may induce responses by interacting with a soluble binding protein in serum that then binds the cell surface protein CD14.

Toll-Like Receptor Signaling Pathways

2014-09-25

Takumi Kawasaki , Taro Kawai

Toll-like receptors (TLRs) play crucial roles in the innate immune system by recognizing pathogen-associated molecular patterns derived from various microbes. TLRs signal through the recruitment of specific adaptor molecules, leading … Toll-like receptors (TLRs) play crucial roles in the innate immune system by recognizing pathogen-associated molecular patterns derived from various microbes. TLRs signal through the recruitment of specific adaptor molecules, leading to activation of the transcription factors NF-κB and IRFs, which dictate the outcome of innate immune responses. During the past decade, the precise mechanisms underlying TLR signaling have been clarified by various approaches involving genetic, biochemical, structural, cell biological and bioinformatics studies. TLR signaling appears to be divergent and to play important roles in many aspects of the innate immune responses to given pathogens. In this review, we describe recent progress in our understanding of TLR signaling regulation and its contributions to host defense.

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What's wrong with Bonferroni adjustments

1998-04-18

Thomas Perneger

Abnormal T cell responses to commensal bacteria are involved in the pathogenesis of inflammatory bowel disease. MyD88 is an essential signal transducer for TLRs in response to the microflora. We … Abnormal T cell responses to commensal bacteria are involved in the pathogenesis of inflammatory bowel disease. MyD88 is an essential signal transducer for TLRs in response to the microflora. We hypothesized that TLR signaling via MyD88 was important for effector T cell responses in the intestine. TLR expression on murine T cells was examined by flow cytometry. CD4+CD45Rbhigh T cells and/or CD4+CD45RblowCD25+ regulatory T cells were isolated and adoptively transferred to RAG1−/− mice. Colitis was assessed by changes in body weight and histology score. Cytokine production was assessed by ELISA. In vitro proliferation of T cells was assessed by [3H]thymidine assay. In vivo proliferation of T cells was assessed by BrdU and CFSE labeling. CD4+CD45Rbhigh T cells expressed TLR2, TLR4, TLR9, and TLR3, and TLR ligands could act as costimulatory molecules. MyD88−/− CD4+ T cells showed decreased proliferation compared with WT CD4+ T cells both in vivo and in vitro. CD4+CD45Rbhigh T cells from MyD88−/− mice did not induce wasting disease when transferred into RAG1−/− recipients. Lamina propria CD4+ T cell expression of IL-2 and IL-17 and colonic expression of IL-6 and IL-23 were significantly lower in mice receiving MyD88−/− cells than mice receiving WT cells. In vitro, MyD88−/− T cells were blunted in their ability to secrete IL-17 but not IFN-γ. Absence of MyD88 in CD4+CD45Rbhigh cells results in defective T cell function, especially Th17 differentiation. These results suggest a role for TLR signaling by T cells in the development of inflammatory bowel disease.

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Sterile inflammation: sensing and reacting to damage

2010-11-19

Grace Chen , Gabriel Núñez

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Targeted disruption of the mouse transforming growth factor-β1 gene results in multifocal inflammatory disease

1992-10-01

Marcia M. Shull , Ilona Ormsby , Ann B. Kier +7 more

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TLR signaling pathways

2004-01-25

Kiyoshi Takeda , Shizuo Akira

An endotoxin-induced serum factor that causes necrosis of tumors.

1975-09-01

E A Carswell , Lloyd J. Old , Robert Kassel +3 more

In studying "hemorrhagic necrosis" of tumors produced by endotoxin, it was found that the serum of bacillus Calmette--Guerin (BCG)-infected mice treated with endotoxin contains a substance (tumor necrosis factor; TNF) … In studying "hemorrhagic necrosis" of tumors produced by endotoxin, it was found that the serum of bacillus Calmette--Guerin (BCG)-infected mice treated with endotoxin contains a substance (tumor necrosis factor; TNF) which mimics the tumor necrotic action of endotoxin itself. TNF-positive serum is as effective as endotoxin itself in causing necrosis of the sarcoma Meth A and other transplanted tumors. A variety of tests indicate that TNF is not residual endotoxin, but a factor released from host cells, probably macrophages, by endotoxin. Corynebacteria and Zymosan, which like BCG induce hyperplasia of the reticulo-endothelial system, can substitute for BCG in priming mice for release of TNF by endotoxin. TNF is toxic in vitro for two neoplastic cell lines; it is not toxic for mouse embryo cultures. We propose that TNF mediates endotoxin-induced tumor necrosis, and that it may be responsible for the suppression of transformed cells by activated macrophages.

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Differential Roles of TLR2 and TLR4 in Recognition of Gram-Negative and Gram-Positive Bacterial Cell Wall Components

1999-10-01

Osamu Takeuchi , Katsuaki Hoshino , Taro Kawai +5 more

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LPS/TLR4 signal transduction pathway

2008-03-07

Yong‐Chen Lu , Wen‐Chen Yeh , Pamela S. Ohashi

Recognition of double-stranded RNA and activation of NF-κB by Toll-like receptor 3

2001-10-01

Lena Alexopoulou , Agnieszka Czopik Holt , Ruslan Medzhitov +1 more

Recognition of Commensal Microflora by Toll-Like Receptors Is Required for Intestinal Homeostasis

2004-07-01

Seth Rakoff-Nahoum , Justin C. Paglino , Fatima Eslami-Varzaneh +2 more

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Toll-like receptor control of the adaptive immune responses

2004-09-28

Akiko Iwasaki , Ruslan Medzhitov

Toll-like receptor 4–dependent contribution of the immune system to anticancer chemotherapy and radiotherapy

2007-08-19

Lionel Apétoh , François Ghiringhelli , Antoine Tesnière +7 more

Toll-Like Receptors

2003-03-03

Kiyoshi Takeda , Tsuneyasu Kaisho , Shizuo Akira

The innate immune system in drosophila and mammals senses the invasion of microorganisms using the family of Toll receptors, stimulation of which initiates a range of host defense mechanisms. In … The innate immune system in drosophila and mammals senses the invasion of microorganisms using the family of Toll receptors, stimulation of which initiates a range of host defense mechanisms. In drosophila antimicrobial responses rely on two signaling pathways: the Toll pathway and the IMD pathway. In mammals there are at least 10 members of the Toll-like receptor (TLR) family that recognize specific components conserved among microorganisms. Activation of the TLRs leads not only to the induction of inflammatory responses but also to the development of antigen-specific adaptive immunity. The TLR-induced inflammatory response is dependent on a common signaling pathway that is mediated by the adaptor molecule MyD88. However, there is evidence for additional pathways that mediate TLR ligand-specific biological responses.

Pathogen Recognition and Inflammatory Signaling in Innate Immune Defenses

2009-04-01

Trine H. Mogensen

SUMMARY The innate immune system constitutes the first line of defense against invading microbial pathogens and relies on a large family of pattern recognition receptors (PRRs), which detect distinct evolutionarily … SUMMARY The innate immune system constitutes the first line of defense against invading microbial pathogens and relies on a large family of pattern recognition receptors (PRRs), which detect distinct evolutionarily conserved structures on pathogens, termed pathogen-associated molecular patterns (PAMPs). Among the PRRs, the Toll-like receptors have been studied most extensively. Upon PAMP engagement, PRRs trigger intracellular signaling cascades ultimately culminating in the expression of a variety of proinflammatory molecules, which together orchestrate the early host response to infection, and also is a prerequisite for the subsequent activation and shaping of adaptive immunity. In order to avoid immunopathology, this system is tightly regulated by a number of endogenous molecules that limit the magnitude and duration of the inflammatory response. Moreover, pathogenic microbes have developed sophisticated molecular strategies to subvert host defenses by interfering with molecules involved in inflammatory signaling. This review presents current knowledge on pathogen recognition through different families of PRRs and the increasingly complex signaling pathways responsible for activation of an inflammatory and antimicrobial response. Moreover, medical implications are discussed, including the role of PRRs in primary immunodeficiencies and in the pathogenesis of infectious and autoimmune diseases, as well as the possibilities for translation into clinical and therapeutic applications.

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The role of pattern-recognition receptors in innate immunity: update on Toll-like receptors

2010-04-20

Taro Kawai , Shizuo Akira

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Recognition of microorganisms and activation of the immune response

2007-10-01

Ruslan Medzhitov

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The family of five: TIR-domain-containing adaptors in Toll-like receptor signalling

2007-04-25

Luke O'neill , Andrew Bowie

CpG Motifs in Bacterial DNA and Their Immune Effects

2002-04-01

Arthur Μ. Krieg

Unmethylated CpG motifs are prevalent in bacterial but not vertebrate genomic DNAs. Oligodeoxynucleotides (ODN) containing CpG motifs activate host defense mechanisms leading to innate and acquired immune responses. The recognition … Unmethylated CpG motifs are prevalent in bacterial but not vertebrate genomic DNAs. Oligodeoxynucleotides (ODN) containing CpG motifs activate host defense mechanisms leading to innate and acquired immune responses. The recognition of CpG motifs requires Toll-like receptor (TLR) 9, which triggers alterations in cellular redox balance and the induction of cell signaling pathways including the mitogen activated protein kinases (MAPKs) and NF kappa B. Cells that express TLR-9, which include plasmacytoid dendritic cells (PDCs) and B cells, produce Th1-like proinflammatory cytokines, interferons, and chemokines. Certain CpG motifs (CpG-A) are especially potent at activating NK cells and inducing IFN-alpha production by PDCs, while other motifs (CpG-B) are especially potent B cell activators. CpG-induced activation of innate immunity protects against lethal challenge with a wide variety of pathogens, and has therapeutic activity in murine models of cancer and allergy. CpG ODN also enhance the development of acquired immune responses for prophylactic and therapeutic vaccination.

Defective LPS Signaling in C3H/HeJ and C57BL/10ScCr Mice: Mutations in Tlr4 Gene

1998-12-11

Alexander Poltorak , Xiaolong He , Irina Smirnova +7 more

Mutations of the gene Lps selectively impede lipopolysaccharide (LPS) signal transduction in C3H/HeJ and C57BL/10ScCr mice, rendering them resistant to endotoxin yet highly susceptible to Gram-negative infection. The codominant Lps … Mutations of the gene Lps selectively impede lipopolysaccharide (LPS) signal transduction in C3H/HeJ and C57BL/10ScCr mice, rendering them resistant to endotoxin yet highly susceptible to Gram-negative infection. The codominant Lps d allele of C3H/HeJ mice was shown to correspond to a missense mutation in the third exon of the Toll-like receptor-4 gene ( Tlr4 ), predicted to replace proline with histidine at position 712 of the polypeptide chain. C57BL/10ScCr mice are homozygous for a null mutation of Tlr4 . Thus, the mammalian Tlr4 protein has been adapted primarily to subserve the recognition of LPS and presumably transduces the LPS signal across the plasma membrane. Destructive mutations of Tlr4 predispose to the development of Gram-negative sepsis, leaving most aspects of immune function intact.

Role of Adaptor TRIF in the MyD88-Independent Toll-Like Receptor Signaling Pathway

2003-07-15

Masahiro Yamamoto , Shintaro Sato , Hiroaki Hemmi +7 more

Stimulation of Toll-like receptors (TLRs) triggers activation of a common MyD88-dependent signaling pathway as well as a MyD88-independent pathway that is unique to TLR3 and TLR4 signaling pathways leading to … Stimulation of Toll-like receptors (TLRs) triggers activation of a common MyD88-dependent signaling pathway as well as a MyD88-independent pathway that is unique to TLR3 and TLR4 signaling pathways leading to interferon (IFN)-β production. Here we disrupted the gene encoding a Toll/IL-1 receptor (TIR) domain-containing adaptor, TRIF. TRIF-deficient mice were defective in both TLR3- and TLR4-mediated expression of IFN-β and activation of IRF-3. Furthermore, inflammatory cytokine production in response to the TLR4 ligand, but not to other TLR ligands, was severely impaired in TRIF-deficient macrophages. Mice deficient in both MyD88 and TRIF showed complete loss of nuclear factor kappa B activation in response to TLR4 stimulation. These findings demonstrate that TRIF is essential for TLR3- and TLR4-mediated signaling pathways facilitating mammalian antiviral host defense.

Innate Immune Recognition

2002-04-01

Charles A. Janeway , Ruslan Medzhitov

The innate immune system is a universal and ancient form of host defense against infection. Innate immune recognition relies on a limited number of germline-encoded receptors. These receptors evolved to … The innate immune system is a universal and ancient form of host defense against infection. Innate immune recognition relies on a limited number of germline-encoded receptors. These receptors evolved to recognize conserved products of microbial metabolism produced by microbial pathogens, but not by the host. Recognition of these molecular structures allows the immune system to distinguish infectious nonself from noninfectious self. Toll-like receptors play a major role in pathogen recognition and initiation of inflammatory and immune responses. Stimulation of Toll-like receptors by microbial products leads to the activation of signaling pathways that result in the induction of antimicrobial genes and inflammatory cytokines. In addition, stimulation of Toll-like receptors triggers dendritic cell maturation and results in the induction of costimulatory molecules and increased antigen-presenting capacity. Thus, microbial recognition by Toll-like receptors helps to direct adaptive immune responses to antigens derived from microbial pathogens.

Circulating mitochondrial DAMPs cause inflammatory responses to injury

2010-03-01

Qin Zhang , Mustafa Raoof , Yu Chen +6 more

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CELLULAR RESPONSES TO INTERFERON-γ

1997-04-01

Ulrich Boehm , Thorsten Klamp , M. de Groot +1 more

The phytohemagglutinin-induced virus-inhibitor may, however, be produced in white cells in response to a stimulation of cellular RNA synthesis and may be a feedback mechanism for control of RNA synthesis. … The phytohemagglutinin-induced virus-inhibitor may, however, be produced in white cells in response to a stimulation of cellular RNA synthesis and may be a feedback mechanism for control of RNA synthesis. E. Frederick Wheelock (1965) ▪ Abstract Interferons are cytokines that play a complex and central role in the resistance of mammalian hosts to pathogens. Type I interferon (IFN-α and IFN-β) is secreted by virus-infected cells. Immune, type II, or γ-interferon (IFN-γ) is secreted by thymus-derived (T) cells under certain conditions of activation and by natural killer (NK) cells. Although originally defined as an agent with direct antiviral activity, the properties of IFN-γ include regulation of several aspects of the immune response, stimulation of bactericidal activity of phagocytes, stimulation of antigen presentation through class I and class II major histocompatibility complex (MHC) molecules, orchestration of leukocyte-endothelium interactions, effects on cell proliferation and apoptosis, as well as the stimulation and repression of a variety of genes whose functional significance remains obscure. The implementation of such a variety of effects by a single cytokine is achieved by complex patterns of cell-specific gene regulation: Several IFN-γ-regulated genes are themselves components of transcription factors. The IFN-γ response is itself regulated by interaction with responses to other cytokines including IFN-α/β, TNF-α, and IL-4. Over 200 genes are now known to be regulated by IFN-γ and they are listed in a World Wide Web document that accompanies this review. However, much of the cellular response to IFN-γ can be described in terms of a set of integrated molecular programs underlying well-defined physiological systems, for example the induction of efficient antigen processing for MHC-mediated antigen presentation, which play clearly defined roles in pathogen resistance. A promising approach to the complexity of the IFN-γ response is to extend the analysis of the less understood IFN-γ-regulated genes in terms of molecular programs functional in pathogen resistance.

Toll-like receptors in innate immunity

2004-11-22

Kiyoshi Takeda , Shizuo Akira

Functional characterization of Toll-like receptors (TLRs) has established that innate immunity is a skillful system that detects invasion of microbial pathogens. Recognition of microbial components by TLRs initiates signal transduction … Functional characterization of Toll-like receptors (TLRs) has established that innate immunity is a skillful system that detects invasion of microbial pathogens. Recognition of microbial components by TLRs initiates signal transduction pathways, which triggers expression of genes. These gene products control innate immune responses and further instruct development of antigen-specific acquired immunity. TLR signaling pathways are finely regulated by TIR domain-containing adaptors, such as MyD88, TIRAP/Mal, TRIF and TRAM. Differential utilization of these TIR domain-containing adaptors provides specificity of individual TLR-mediated signaling pathways. Several mechanisms have been elucidated that negatively control TLR signaling pathways, and thereby prevent overactivation of innate immunity leading to fatal immune disorders. The involvement of TLR-mediated pathways in autoimmune and inflammatory diseases has been proposed. Thus, TLR-mediated activation of innate immunity controls not only host defense against pathogens but also immune disorders.

HMG-1 as a Late Mediator of Endotoxin Lethality in Mice

1999-07-09

Haichao Wang , Ona Bloom , Minghuang Zhang +7 more

Endotoxin, a constituent of Gram-negative bacteria, stimulates macrophages to release large quantities of tumor necrosis factor (TNF) and interleukin-1 (IL-1), which can precipitate tissue injury and lethal shock (endotoxemia). Antagonists … Endotoxin, a constituent of Gram-negative bacteria, stimulates macrophages to release large quantities of tumor necrosis factor (TNF) and interleukin-1 (IL-1), which can precipitate tissue injury and lethal shock (endotoxemia). Antagonists of TNF and IL-1 have shown limited efficacy in clinical trials, possibly because these cytokines are early mediators in pathogenesis. Here a potential late mediator of lethality is identified and characterized in a mouse model. High mobility group–1 (HMG-1) protein was found to be released by cultured macrophages more than 8 hours after stimulation with endotoxin, TNF, or IL-1. Mice showed increased serum levels of HMG-1 from 8 to 32 hours after endotoxin exposure. Delayed administration of antibodies to HMG-1 attenuated endotoxin lethality in mice, and administration of HMG-1 itself was lethal. Septic patients who succumbed to infection had increased serum HMG-1 levels, suggesting that this protein warrants investigation as a therapeutic target.

Immunological and Inflammatory Functions of the Interleukin-1 Family

2009-03-20

Charles A. Dinarello

More than any other cytokine family, the interleukin (IL)-1 family is closely linked to the innate immune response. This linkage became evident upon the discovery that the cytoplasmic domain of … More than any other cytokine family, the interleukin (IL)-1 family is closely linked to the innate immune response. This linkage became evident upon the discovery that the cytoplasmic domain of the IL-1 receptor type I is highly homologous to the cytoplasmic domains of all Toll-like receptors (TLRs). Thus, fundamental inflammatory responses such as the induction of cyclooxygenase type 2, increased expression of adhesion molecules, or synthesis of nitric oxide are indistinguishable responses of both IL-1 and TLR ligands. Both families nonspecifically affect antigen recognition and lymphocyte function. IL-1β is the most studied member of the IL-1 family because of its role in mediating autoinflammatory diseases. Although the TLR and IL-1 families evolved to assist in host defense against infection, unlike the TLR family, the IL-1 family also includes members that suppress inflammation, both specifically within the IL-1 family but also nonspecifically for TLR ligands and the innate immune response.

Interferon-γ: an overview of signals, mechanisms and functions

2003-10-02

Kate Schroder , Paul J. Hertzog , Timothy Ravasi +1 more

Abstract Interferon-γ (IFN-γ) coordinates a diverse array of cellular programs through transcriptional regulation of immunologically relevant genes. This article reviews the current understanding of IFN-γ ligand, receptor, ignal transduction, and … Abstract Interferon-γ (IFN-γ) coordinates a diverse array of cellular programs through transcriptional regulation of immunologically relevant genes. This article reviews the current understanding of IFN-γ ligand, receptor, ignal transduction, and cellular effects with a focus on macrophage responses and to a lesser extent, responses from other cell types that influence macrophage function during infection. The current model for IFN-γ signal transduction is discussed, as well as signal regulation and factors conferring signal specificity. Cellular effects of IFN-γ are described, including up-regulation of pathogen recognition, antigen processing and presentation, the antiviral state, inhibition of cellular proliferation and effects on apoptosis, activation of microbicidal effector functions, immunomodulation, and leukocyte trafficking. In addition, integration of signaling and response with other cytokines and pathogen-associated molecular patterns, such as tumor necrosis factor-α, interleukin-4, type I IFNs, and lipopolysaccharide are discussed.

Lipopolysaccharide Endotoxins

2002-06-01

Christian R.H. Raetz , Chris Whitfield

▪ Abstract Bacterial lipopolysaccharides (LPS) typically consist of a hydrophobic domain known as lipid A (or endotoxin), a nonrepeating “core” oligosaccharide, and a distal polysaccharide (or O-antigen). Recent genomic data … ▪ Abstract Bacterial lipopolysaccharides (LPS) typically consist of a hydrophobic domain known as lipid A (or endotoxin), a nonrepeating “core” oligosaccharide, and a distal polysaccharide (or O-antigen). Recent genomic data have facilitated study of LPS assembly in diverse Gram-negative bacteria, many of which are human or plant pathogens, and have established the importance of lateral gene transfer in generating structural diversity of O-antigens. Many enzymes of lipid A biosynthesis like LpxC have been validated as targets for development of new antibiotics. Key genes for lipid A biosynthesis have unexpectedly also been found in higher plants, indicating that eukaryotic lipid A-like molecules may exist. Most significant has been the identification of the plasma membrane protein TLR4 as the lipid A signaling receptor of animal cells. TLR4 belongs to a family of innate immunity receptors that possess a large extracellular domain of leucine-rich repeats, a single trans-membrane segment, and a smaller cytoplasmic signaling region that engages the adaptor protein MyD88. The expanding knowledge of TLR4 specificity and its downstream signaling pathways should provide new opportunities for blocking inflammation associated with infection.

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A Multigenerational ″Dirty″ Mouse Model for Studying Trauma-Induced Immune Dysregulation and Infection Susceptibility

2025-06-24

Alexandria Byskosh , John Pulford , Ekaterina Murzin +7 more | bioRxiv (Cold Spring Harbor Laboratory)

Background: Trauma induces immune dysregulation in both humans and mice, increasing infection susceptibility. Mouse models are critical in research but have been criticized for lacking translational relevance. This study tested … Background: Trauma induces immune dysregulation in both humans and mice, increasing infection susceptibility. Mouse models are critical in research but have been criticized for lacking translational relevance. This study tested whether multigenerational ″natural immune″ (NI) mice — generated by co-housing C57BL/6 mice with ″dirty″ pet shop mice and breeding through multiple generations — would develop a more human-like immune response to trauma and infection than ″clean″ specific pathogen-free (SPF) C57BL/6 mice whose immune systems developed without normal flora. Methods: To address this gap, SPF and NI mice underwent burn trauma followed by Pseudomonas aeruginosa lung infection. Peripheral blood and bone marrow immune cells were characterized by flow cytometry and mass cytometry (CyTOF). Blood samples from trauma patients were analyzed for comparison. Results: At baseline, NI mice exhibited more neutrophils compared to SPF mice, closer resembling human peripheral immune composition. Following injury, SPF mice demonstrated increased blood neutrophils and monocytes with reduced B and T cells, whereas NI mice exhibited a muted blood immune cell response. In contrast, NI mice showed a robust emergency granulopoiesis response and preserved hematopoietic stem cells (HSCs) following secondary infection, whereas HSCs decreased in SPF mice. Time-matched blood samples from human trauma patients revealed alterations more closely resembling those observed in NI mice. Conclusions: These findings support the hypothesis that NI mice develop a more human-like immune response to trauma and infection than SPF mice. This suggests that NI mice may provide a more translationally relevant platform for studying trauma-induced immune dysfunction and infection susceptibility mechanisms.

SPI1 upregulated LILRB2 to enhance the immunosuppressive phenotype of LPS-tolerant macrophages by inhibiting TLR8-mediated MyD88/NF-κB signaling

2025-06-23

Ruojing Bai , Jun Guo | Biology Direct

In sepsis, immunosuppression is commonly observed as lipopolysaccharide (LPS) tolerance in macrophages. Leukocyte immunoglobulin-like receptor B2 (LILRB2) is an inhibitory receptor on immune cells that may play a crucial role … In sepsis, immunosuppression is commonly observed as lipopolysaccharide (LPS) tolerance in macrophages. Leukocyte immunoglobulin-like receptor B2 (LILRB2) is an inhibitory receptor on immune cells that may play a crucial role in the immunosuppressive phenotype of LPS-tolerant macrophages, although its exact function in sepsis remains unclear. In this study, macrophages were exposed to single or sequential LPS doses to induce LPS stimulation or tolerance. Cell viability was assessed using CCK-8 assay, apoptosis, and macrophage polarization were detected by flow cytometry, and pro-inflammatory cytokine levels were measured by RT-qPCR and ELISA. Molecular interactions were explored using Co-IP, ChIP, and dual-luciferase assays, while mRNA and protein expression were assessed by RT-qPCR and Western blotting. The results showed that LILRB2 was upregulated in macrophages following LPS stimulation, with a more significant increase in the LPS-tolerant group. Knocking down LILRB2 reversed the immunosuppressive phenotype of LPS-tolerant macrophages and restored the inhibition of MyD88/NF-κB signaling and p65 nuclear translocation caused by LPS tolerance. Mechanistically, LILRB2 interacted with Toll-like receptor 8 (TLR8) to inhibit the MyD88/NF-κB signaling pathway in LPS-tolerant macrophages. Furthermore, the upregulation of the Spi-1 proto-oncogene (SPI1) enhanced the immunosuppressive phenotype by transcriptionally activating LILRB2. In conclusion, SPI1 upregulation promoted the immunosuppressive phenotype of LPS-tolerant macrophages by activating LILRB2 transcription, which inhibited TLR8-mediated MyD88/NF-κB signaling. This study clarifies the role of LILRB2 and its underlying mechanisms in LPS-tolerant macrophages.

The monomeric but not homotrimeric spike protein of SARS-CoV-2 activates TLR4 signaling

2025-06-23

Charlotte Lübow , Günther Weindl | Molecular Biology Reports

TLR9 Downregulation in Breast Cancer: Its Role in Tumor Immunity, Inflammatory Response, and Cellular Senescence

2025-06-23

Emily Sible , Gregory Weitsman , Salome Amouyal +7 more | Journal of Innate Immunity

Toll-like receptor 9 (TLR9) is primarily expressed in human dendritic and B cells and recognizes double-stranded DNA motifs from pathogens to initiate an inflammatory response. Recent studies have revealed TLR9's … Toll-like receptor 9 (TLR9) is primarily expressed in human dendritic and B cells and recognizes double-stranded DNA motifs from pathogens to initiate an inflammatory response. Recent studies have revealed TLR9's involvement beyond its conventional role in the immune response, notably during the tumorigenesis of various cancers such as head and neck, cervical, and ovarian cancers. In this study, immunohistochemistry (IHC) analysis demonstrated significantly lower TLR9 levels in breast cancer tumors compared to normal breast tissue epithelium. This downregulation was also observed in several transformed breast cancer cell lines compared to untransformed breast epithelial cell lines. Furthermore, MDA-MB-361 breast cancer cells expressing exogenous TLR9 exhibited reduced colony growth and an increase in senescence marker IL-6, pro- inflammatory cytokine CCL2, CXCL1 chemokine; and growth factor GM-CSF. These findings support TLR9's regulatory role in mitigating breast cancer and highlight its critical connection between the innate immunity and tumor cell growth.

IRRITATION TEST OF LIQUID ANTIBACTERIAL SOAP COMBINING LEGUNDI AND GREEN BETEL LEAVE EXTRACTS ON WHITE RATS (Rattus norvegicus)

2025-06-22

Ida Bagus Oka Suyasa , Ni Nyoman Astika Dewi , Made Delia Budi Apriliapatni +1 more | Meditory The Journal of Medical Laboratory

Background: Soap is a cleanser that is made with a chemical reaction. Soap preparations with active ingredients derived from nature are also widely circulated. Natural ingredients that have many active … Background: Soap is a cleanser that is made with a chemical reaction. Soap preparations with active ingredients derived from nature are also widely circulated. Natural ingredients that have many active substances are legundi leaves and green betel leaves. Two antimicrobial agents from these ingredients working simultaneously on a homogeneous microbial population will have a synergistic effect.Objective: This study aims to determine the safety of using an antibacterial liquid soap formula with a combination of legundi and betel leaf extracts.Methods: This study is an experimental research that includes physicochemical testing of the soap formula, organoleptic evaluation, and irritation testing on white rats (Rattus norvegicus) using the Draize method with a posttest-only control group design. This research was analyzed descriptively. This study adheres to the ethical principle of beneficence, prioritizing the well-being and safety of all participants.Results: Organoleptic test, pH test, homogeneity test, and water content test meet Indonesian National Standard requirements, and there is no irritation in experimental animals.Conclusions: An antibacterial liquid soap formula with a combination of legundi and betel leaf extracts is safe.

Inhibiting the expression of GPR43 in macrophages can alleviate osteoarthritis by suppressing the M1 polarization and suppressing ROS production

2025-06-21

Haokun Mo , Yanjun Hou , Junchen He +6 more | International Immunopharmacology

G-protein-coupled receptor 43 (GPR43) plays an important role in immunomodulation, metabolic regulation and ROS production. Our research aims to explore the role and mechanism of GPR43 in osteoarthritis (OA). We … G-protein-coupled receptor 43 (GPR43) plays an important role in immunomodulation, metabolic regulation and ROS production. Our research aims to explore the role and mechanism of GPR43 in osteoarthritis (OA). We experimentally determined that following the intervention of macrophages with lipopolysaccharide (LPS), there is a significant upregulation in the expression of GPR43. GPR43 knockdown in macrophages can inhibit the M1 polarization and reactive oxygen species (ROS) production. Meanwhile, GPR43 knockdown can alleviate osteoarthritis in destabilized medial meniscus (DMM) induced OA mouse models. In mechanism, GPR43 knockdown in macrophages can inhibit the expression of CX3C chemokine ligand 1 (CX3CL1) and the activation of NF-κB signaling pathway, thereby exerting a therapeutic effect on OA. Overall, knockdown of GPR43 in macrophages can alleviate OA by inhibiting M1 polarization and ROS production via the CX3CL1/NF-κB signaling pathway. GPR43 is a potential therapeutic target for OA.

NOMO-1 cells expressing an NF-κB luciferase reporter gene facilitate a simple, rapid monocyte activation test that can detect a wide range of pyrogens

2025-06-20

Tomohisa Nanao , Yuki Marutani , Katsuko Sato +4 more | PLoS ONE

Pyrogens, which include endotoxin and non-endotoxin pyrogens (NEPs), act on immune cells in the bloodstream, causing various effects such as fever and endotoxic shock. The limulus amebocyte lysate test, a … Pyrogens, which include endotoxin and non-endotoxin pyrogens (NEPs), act on immune cells in the bloodstream, causing various effects such as fever and endotoxic shock. The limulus amebocyte lysate test, a commonly used endotoxin test in the manufacturing of pharmaceuticals and medical devices, can detect endotoxin but not NEPs. The monocyte activation test (MAT), which uses monocytes, is a testing method included in the European Pharmacopoeia (EP 11.5; 07/2024:20630) that can detect NEPs. The MAT detects the cellular response following activation of Toll-like receptors (TLRs) by pyrogens; released cytokines, such as IL-6, are often the targets of detection. This cytokine release is regulated by the transcription factor NF-κB. In this study, we investigated whether it is possible to detect pyrogens with an NF-κB reporter gene-expressing cell line, using the NOMO-1 cell line as a model monocyte-like line. This study demonstrates that the reporter gene-expressing cells can detect 0.0125 EU/mL lipopolysaccharide (LPS) after 3 hours of incubation, and a stable calibration curve for LPS quantification can be created. Moreover, these cells can detect agonists for TLR1–9 in a concentration-dependent manner. Pharmaceuticals, including blood products and antibody drugs, were used in LPS recovery tests to confirm that they do not interfere with LPS detection. This study demonstrates that NF-κB reporter cells facilitate a simpler, more concise MAT, eliminating the complexity associated with enzyme-linked immunosorbent assays. Moreover, using the NOMO-1 cell line allows for the detection of a wider range of NEPs compared with using existing reporter gene-expressing cell lines.

A pilot study on long-term observation of septic mice: history of severe infections may accelerate host senescence even 18 months later

2025-06-20

Masafumi Saito , Yuko Ono , Yoshihisa Fujinami +5 more | Shock

Klebsiella pneumoniae remodels its Kdo2-lipid A in a TLR4-dependent manner to adapt to the macrophage intracellular environment

2025-06-20

Toby Leigh Bartholomew , Joana Sá‐Pessoa , Rebecca Lancaster +6 more | bioRxiv (Cold Spring Harbor Laboratory)

SUMMARY Pathogen adaptations to the intracellular macrophage environment remain poorly understood. We performed a high-resolution structural analysis of the lipid A purified from intracellular Klebsiella pneumoniae (KP). In both mouse … SUMMARY Pathogen adaptations to the intracellular macrophage environment remain poorly understood. We performed a high-resolution structural analysis of the lipid A purified from intracellular Klebsiella pneumoniae (KP). In both mouse and human macrophages, KP produces hexa- and hepta-acylated lipid A species modified with palmitate and 2-hydroxylated. LpxL1, PagP, and LpxO enzymes govern the intracellular lipid A in a PhoPQ-dependent manner triggered by the acidic pH of the KP-containing vacuole (KCV). Absence of LpxO and PagP lipid A modifications impairs intracellular survival and heightens NF-κB and IRF3-mediated inflammation, though KCV maturation remains unaffected. Instead, these modifications fortify the bacterial membrane. Absence of TLR4-TRAM-TRIF signalling increases KCV pH, impairing the production of the intracellular lipid A. KP intracellular survival is reduced in tlr4 -/- macrophages, highlighting the critical role of this signalling pathway in KP immune evasion and how the pathogen has evolved to rely on innate immune system cues for virulence.

Cytokine-mediated inhibition of Staphylococcus aureus adherence and invasion into nonphagocytic cells

2025-06-20

Arif Luqman , Knut Ohlsen | Medical Microbiology and Immunology

Synergistic optimizations of efficacy and membrane permeability of IRAK4 inhibitors: identifying new lead compounds for anti-inflammatory therapeutics

2025-06-19

Kewon Kim , Ahyoung Jang , Huayun Han +3 more | Journal of Enzyme Inhibition and Medicinal Chemistry

Interleukin-1 receptor-associated kinase 4 (IRAK4) is a serine/threonine kinase that plays a pivotal role in immune signalling and cytokine regulation, making it a compelling target for the treatment of inflammatory … Interleukin-1 receptor-associated kinase 4 (IRAK4) is a serine/threonine kinase that plays a pivotal role in immune signalling and cytokine regulation, making it a compelling target for the treatment of inflammatory and autoimmune diseases. We initiated a drug discovery campaign based on the N2,N4-diphenylpyrimidine-2,4-diamine (DPDA) scaffold, employing an integrated strategy that combined structure-based de novo design, three-dimensional quantitative structure-activity relationship (3D-QSAR) modelling, and biochemical evaluation. This approach emphasised the optimisation of membrane permeability by controlling the 1-octanol/water partition coefficient (LogP), while also enforcing configurational constraints to enhance IRAK4-specific binding. Through iterative cycles of computational modelling and chemical synthesis, we identified 10 out of 17 newly synthesised compounds that exhibited potent IRAK4 inhibition at low-nanomolar concentrations in both enzymatic and cellular assays. Among these, compounds 10 and 13 stood out, demonstrating strong IRAK4 inhibitory activity, favourable membrane permeability, and minimal off-target kinase interactions.

Toll-like Receptors in Immuno-Metabolic Regulation of Emotion and Memory

2025-06-19

Carla Crespo-Quiles , Teresa Femenía | Cells

Toll-like receptors (TLRs) comprise an evolutionarily conserved family of pattern recognition receptors that detect microbial-associated molecular patterns and endogenous danger signals to orchestrate innate immune responses. While traditionally positioned at … Toll-like receptors (TLRs) comprise an evolutionarily conserved family of pattern recognition receptors that detect microbial-associated molecular patterns and endogenous danger signals to orchestrate innate immune responses. While traditionally positioned at the frontline of host defense, accumulating evidence suggests that TLRs are at the nexus of immuno-metabolic regulation and central nervous system (CNS) homeostasis. They regulate a wide range of immune and non-immune functions, such as cytokine and chemokine signaling, and play key roles in modulating synaptic plasticity, neurogenesis, and neuronal survival. However, alterations in TLR signaling can drive a sustained pro-inflammatory state, mitochondrial dysfunction, and oxidative stress, which are highly associated with the disruption of emotional and cognitive functions and the pathogenesis of psychiatric disorders. In this review, we integrate findings from molecular to organismal levels to illustrate the diverse roles of TLRs in regulating emotion, cognition, metabolic balance, and gut-brain interactions. We also explore emerging molecular targets with the potential to guide the development of more effective therapeutic interventions.

Design and Application of Conjugatable Small Molecule Toll-Like Receptor 4 Ligands

2025-06-18

Yuji Mahara , I. Fukuda , Ryutaro Tanaka +7 more | Bioconjugate Chemistry

We identified structurally distinct pyrimido[5,4-b]indole derivatives as toll-like receptor 4 (TLR4) ligands. Previous structure-activity relationship studies revealed that C8-aryl derivatives in pyrimido[5,4-b]indole, especially phenyl and 2-naphthyl compounds, are more potent … We identified structurally distinct pyrimido[5,4-b]indole derivatives as toll-like receptor 4 (TLR4) ligands. Previous structure-activity relationship studies revealed that C8-aryl derivatives in pyrimido[5,4-b]indole, especially phenyl and 2-naphthyl compounds, are more potent in the activation of TLR4 signaling. Molecular modeling of these compounds indicated that C8-aryl groups are important for the interaction of the TLR4/myeloid differentiation factor-2 (MD-2) complex. Additionally, the modeling suggested that the N5 position in pyrimido[5,4-b]indole could be used as a further modification site to develop various drug conjugates. In this study, we examined whether the N5 position in pyrimido[5,4-b]indole can be used for conjugation without losing potency. Since tetraethylene glycol (TEG) derivatives at the N5 position were predicted to bind to TLR4/MD-2 complex using in silico molecular docking analysis, the compounds with the TEG group at the N5 position were synthesized and evaluated for immunostimulatory activity by human TLR4 reporter cell assay. As a result of fine-tuning of the C8 substitution groups, we found that TLR4 ligand (TLR4L) 10 with a 3-thienylethynyl group at the C8 position maintained TLR4 potency and demonstrated agonistic activity in primary murine bone marrow dendritic cells (mBMDC) and human TLR4 reporter HEK-Blue cells. TLR4L 10 was conjugated to sugar-immobilized gold nanoparticles (SGNPs) by introducing thioctic acid as a spacer into the TEG moiety. The obtained TLR4L-SGNPs 17 were taken up and showed agonistic activity in mBMDC. Thus, our designed TLR4L 10 and TLR4L-SGNP 17 are new candidates as immunomodulators for novel class adjuvant systems.

TLR3-mediated NET formation and macrophage activation in acute liver failure: Targeting IL-36 signaling to attenuate inflammatory drivers

2025-06-18

Zhihong Zhang , Hongxu Yang , Junliang Yang +6 more | International Immunopharmacology

Peptidoglycan derived from Lacticaseibacillus rhamnosus and Lactobacillus acidophilus suppress TLR2/1-mediated inflammation in bovine endometrial epithelial cells

2025-06-18

Elham Waehama , Kenji Fukuda , A. Mansouri +4 more | Frontiers in Immunology

Bacteria and associated products are factors in the pathogenesis of bovine endometrial inflammation, contributing to reproductive dysfunction. While peptidoglycan derived from Staphylococcus aureus (PGN-Sa) has been demonstrated to induce pro-inflammatory … Bacteria and associated products are factors in the pathogenesis of bovine endometrial inflammation, contributing to reproductive dysfunction. While peptidoglycan derived from Staphylococcus aureus (PGN-Sa) has been demonstrated to induce pro-inflammatory responses and disrupt sperm–immune interactions in bovine endometrial epithelial cells (BEECs) via Toll-like receptor 2/1 (TLR2/1), the immunomodulatory potential of peptidoglycan from lactic acid bacteria (LAB) within the female reproductive tract remains unexplored. This study investigated the in vitro immunomodulatory effects of LAB-derived peptidoglycan (PGN-L) on TLR2/1-mediated inflammation in BEECs, with the specific TLR2/1 agonist PAM3CSK4 (PAM3) as an inflammatory stimulus. PGN-L was extracted and characterized from Lacticaseibacillus rhamnosus (PGN-Lr) and Lactobacillus acidophilus (PGN-La), and its structural composition was compared to that of commercial PGN-Sa. Subsequently, BEECs were pre-incubated with PGN-L (Lr, La) or PGN-Sa (1 ng/mL) for 24 h before stimulation with PAM3 (100 ng/mL) for 3 h. The expression of inflammatory genes ( TNF , CXCL8 , IL1B , and PTGES ) and TLRs ( TLR1 , TLR2 , TLR4 , and TLR6 ) was quantified by RT-qPCR. The protein expression of TNF, PTGES, and TLR2 was detected using immunofluorescence, while PGE 2 concentrations in the culture media were measured by ELISA. PGN-Lr and PGN-La shared the GlcNAc-MurNAc backbone with PGN-Sa, while PGN-L had a unique modification. PGN-L and PGN-Sa contained lysine at the cross-bridge stem, composed of glycine in PGN-Sa and likely modified D-aspartate in PGN-L. While PGN-Sa and PAM3 significantly upregulated the expression of inflammatory mediators, neither PGN-Lr nor PGN-La alone induced a pro-inflammatory response in BEECs. Importantly, pretreatment with both PGN-Lr and PGN-La significantly reduced PAM3-induced inflammatory gene expression and reduced PGE 2 secretion. In silico molecular findings suggested a potential mechanism whereby PGN-L may act as a TLR2/1 antagonist, contrasting with the agonistic effects of PGN-Sa and PAM3, which promoted TLR2/1 heterodimerization. These findings suggest that PGN-Lr and PGN-La can suppress TLR2/1-mediated uterine inflammation in vitro , by potentially modulating TLR2/1 signaling in BEECs. Further investigation of PGN-L holds promise for the development of therapeutic strategies to enhance bovine reproductive efficiency.

Interplay of trauma-triggered auto-inflammation and T-cell auto-reactivity in posttraumatic dystrophy

2025-06-18

E. Scola | Frontiers in Immunology

Damage-associated molecular patterns (DAMPs) cause sterile auto- inflammation after a traumatic incident in human tissues via innate immunity. The auto-reactivity of natural killer T cells (NK-T cells) instigated by DAMP-activated … Damage-associated molecular patterns (DAMPs) cause sterile auto- inflammation after a traumatic incident in human tissues via innate immunity. The auto-reactivity of natural killer T cells (NK-T cells) instigated by DAMP-activated exocytosis of dendritic cell (DC) vesicles forces implementation of T helper cells, which aggravate inflammatory reactions such as AV shunts and hyperperfusion of the ROI with hypoxia of capillaries. For example, in trauma patients, elevated venous pO 2 was found compared to that in the contralateral extremity of &gt; 20 mmHg 2.66 kPa. Scintigraphic perfusion of the ROI showed elevated values of over 90% on average compared with the healthy side. These findings suggest local capillary stasis, hypoxia, and acidosis. In the initial process, macrophages and dendritic cells play an important role, along with DAMPs, in the activation of innate immunity. Additional tissue-homing NKT cells are activated by releasing pro-inflammatory cytokines. The resulting “cytokine storm” opens options for perpetuation by diverse autocrine loops and inflammasomes. Finally, antibodies against self-molecules are directed against cells and tissues. In a biological sense, this represents the worst scenario in chronic-aseptic inflammatory reactions after trauma and must be fought from the beginning to avoid chronification and spreading, which can lead to fibrosis and functional impairment of the injured extremity. This is the feared endpoint of posttraumatic dystrophy.

A Novel Hybrid Peptide VLP-Aβ Efficiently Regulates Immunity by Stimulating Myeloid Differentiation Protein and Activating the NF-κB Pathway

2025-06-18

Junyong Wang , Xuelian Zhao , Rijun Zhang +4 more | International Journal of Molecular Sciences

Immunosuppression dramatically increases tissue and organ susceptibility to infection, injury, and even cancer. This poses a serious threat to human and animal health. In a previous study, we established a … Immunosuppression dramatically increases tissue and organ susceptibility to infection, injury, and even cancer. This poses a serious threat to human and animal health. In a previous study, we established a platform for high-throughput design and screening of multifunctional peptides. Using this platform, we successfully identified a novel hybrid peptide, VLP-Aβ (VA), which exhibits both immunomodulatory and antioxidant properties. This study aimed to evaluate the immunomodulatory activity of VA and investigate the underlying molecular mechanisms. In the cyclophosphamide (CTX)-induced immunodeficient mouse model, VA significantly alleviated CTX-induced weight loss. It also restored thymus and spleen indices, and increased serum immunoglobulins (IgA, IgM, IgG) and cytokines (TNF-α, IL-6, IL-1β) levels. VA also improved splenic lymphocyte proliferation, CD4+/CD8+ T cell ratios, and NK cell cytotoxicity. At the cellular level, western blot analysis showed that VA activated the TLR4-NF-κB pathway in RAW264.7 macrophages. Mechanistically, inhibition of the MD2 protein by L6H21 abolished VA's immunomodulatory effects. This confirms MD2 as a critical mediator. Molecular docking and dynamics simulations revealed that VA binds stably to the hydrophobic pocket of MD2. These findings suggest that VA exerts immunomodulatory effects by stimulating MD2 and activating the TLR4-NF-κB pathway, which provides new ideas, techniques, and approaches for the development of novel peptide immunomodulators.

Development and validation of a sandwich ELISA for equine IL-1β

2025-06-18

Saiwen Ma , Xing Guo , Diqiu Liu +3 more | Animal Diseases

Abstract In this study, we developed a highly sensitive enzyme-linked immunosorbent assay (ELISA) using newly produced monoclonal antibodies (mAbs) for detecting horse/donkey IL-1β in cell culture medium and serum samples. … Abstract In this study, we developed a highly sensitive enzyme-linked immunosorbent assay (ELISA) using newly produced monoclonal antibodies (mAbs) for detecting horse/donkey IL-1β in cell culture medium and serum samples. The mAbs were generated via the use of a KLH-conjugated peptide and purified equine IL-1β protein as separate immunogens. Notably, the generated mAbs (3G8 and 5G3) demonstrated no cross-reactivity with other major inflammatory mediators, including IL-1α, IL-1Ra, TNF-α, and SAA. The IL-1β assay, which is based on the screened mAbs, exhibits a detection range of 200–10,000 pg/mL, meeting clinical detection requirements. The coefficients of variation for the repeatability and reproducibility of the assay were both less than 5%, indicating an acceptable level of variation. Subsequently, 84 equine and 24 asinine serum samples were collected, and the IL-1β concentration was measured with both our assay and a commercial kit in parallel. Our results revealed no significant difference between the in-house and commercial ELISA kits for the detection of IL-1β concentrations in horse sera. Moreover, our ELISA method demonstrated superior sensitivity for IL-1β detection in donkey samples compared to existing commercial assays. These findings suggest that the newly developed ELISA provides a reliable analytical method for detecting IL-1β in both equine and asinine samples.

Endotoxin, Virus and Bacterial Removal: Why, When and How?

2025-06-18

Lui G. Forni , Vedran Premužić | Blood Purification

: Sepsis is defined as a life-threatening organ dysfunction caused by a dysregulated host response to infection and where underlying circulatory, cellular, and metabolic abnormalities contribute to a greater risk … : Sepsis is defined as a life-threatening organ dysfunction caused by a dysregulated host response to infection and where underlying circulatory, cellular, and metabolic abnormalities contribute to a greater risk of mortality than that posed by sepsis alone this may be considered septic shock where circulatory support is needed in the face of a raised lactate level. The main pillars of therapy remain source control and appropriate timely antibiotics, resuscitation where needed and adequate source control. However in the setting of organ failure further support may be needed. Here we discuss the potential benefits from removal of pathogens using available extracorporeal techniques. Although randomised controlled trials supporting such an approach are remin elusive this is due to change in the next few years with current studies being performed.

Optimization, Characterization and Pharmacological Validation of the Endotoxin-Induced Acute Pneumonitis Mouse Model

2025-06-18

Emese Ritter , Kitti Hohl , László Kereskai +7 more | Biomedicines

Background/Objectives: In preclinical research of airway inflammation, the endotoxin (lipopolysaccharide: LPS)-induced acute interstitial pneumonitis is the most commonly used mechanism model. However, studies apply different LPS serotypes, doses, administration routes, … Background/Objectives: In preclinical research of airway inflammation, the endotoxin (lipopolysaccharide: LPS)-induced acute interstitial pneumonitis is the most commonly used mechanism model. However, studies apply different LPS serotypes, doses, administration routes, and reference compounds, making result interpretation challenging and drawing conclusions difficult. Therefore, here we aimed to optimize, characterize, and validate this model with dexamethasone in mice. Methods: Pneumonitis was induced by intratracheal LPS (0.25, 1, 2.5, 5 mg/kg; E. coli O111:B4) in C57BL/6J and NMRI mice; controls received phosphate-buffered saline (PBS). Dexamethasone (5 mg/kg i.p.) was used as a positive control. Respiratory functions were measured by restrained plethysmography 24 h after induction, and core body temperature was monitored. Lungs were excised and weighed, and then myeloperoxidase (MPO) activity and histopathological analysis were performed to assess pulmonary inflammation. Results: LPS-induced significant body weight loss, perivascular pulmonary edema, MPO activity increase, neutrophil infiltration, and respiratory function impairment in a dose-independent manner. However, LPS-induced hypothermia dynamics and duration were dose-dependent. The inhibitory effects of the reference compound dexamethasone were only detectable in the case of the 0.25 mg/kg LPS dose on most inflammatory parameters. These results did not differ substantially between C57BL/6J and NMRI mouse strains. Conclusions: Very low doses of LPS induce characteristic functional and morphological inflammatory alterations in the lung, which do not worsen in response to even 20 times higher doses. Since the effect of pharmacological interventions is likely to be detectable in the case of the 0.25 mg/kg LPS dose, we suggest this protocol for testing novel anti-inflammatory agents.

Mitochondrial DNA oxidation propagates autoimmunity by enabling plasmacytoid dendritic cells to induce TFH differentiation

2025-06-17

Hongxu Xian , Kosuke Watari , Masafumi Ohira +6 more | Nature Immunology

Long-term omega-3 fatty acids modulate immune responses more effectively than ibuprofen in Mtb-infected mice: An in silico functional analysis approach

2025-06-17

S.I. King , Arista Nienaber , Frank Ekow Atta Hayford +4 more | International Immunopharmacology

The Safety of Intravenous Lipopolysaccharide for the Study of Systemic Inflammation in Humans: A Scoping Review

2025-06-16

Unimark Junior S. Awadzi , Ryan Heumann , Grzegorz B. Gmyrek +3 more | medRxiv (Cold Spring Harbor Laboratory)

Background and Objective This review was conducted to evaluate the safety of intravenous lipopolysaccharide (IV LPS) for human immunology research through a scoping assessment of published clinical trials and pertinent … Background and Objective This review was conducted to evaluate the safety of intravenous lipopolysaccharide (IV LPS) for human immunology research through a scoping assessment of published clinical trials and pertinent case reports. As a collection of case studies reporting rare instances of sinus pauses following IV LPS had been reported in 2005, along with suggested approaches to minimize them, we limited our review to articles published since 2005 in order to focus on contemporary safety. Method PRISMA Extension for Scoping Reviews (PRISMA-ScR) guidelines were followed. English language articles meeting inclusion criteria were identified in PubMed through February 2025. Results From 234 articles we identified 155 distinct studies, with the majority (n=113) limiting enrollment to males only. These studies included a total of 3,551 volunteers, almost exclusively healthy volunteers, with an estimated mean age of 26.0 (range 20 to 56). In all studies, IV LPS elicited a dose-dependent inflammatory response characterized by elevations of heart rate, body temperature, and influenza-like symptoms that typically resolved by 8 hours post dosing. The only unanticipated serious adverse events identified were 2 cases of mild syncope associated with 4-5 second sinus pauses that both occurred in a single study. Conclusion The rarity of adverse events across the 155 studies reviewed suggests that the LPS model of systemic inflammation in humans is safe and well tolerated, although precautions should be taken to minimize vagally induced sinus pauses. Keywords lipopolysaccharide, immunology, safety, bradycardia, systemic inflammation, endotoxemia

4-Octyl itaconate alleviates endothelial cell inflammation and barrier dysfunction in LPS-induced sepsis via modulating TLR4/MAPK/NF-κB signaling

2025-06-16

Rong Li , Yu Ma , Haoran Wu +7 more | Molecular Medicine

Abstract Aim Sepsis-induced vascular injury is a major contributor to the high mortality rate of sepsis. However, effective treatments remain elusive due to limited knowledge regarding the underlying molecular mechanisms. … Abstract Aim Sepsis-induced vascular injury is a major contributor to the high mortality rate of sepsis. However, effective treatments remain elusive due to limited knowledge regarding the underlying molecular mechanisms. Itaconic acid, an endogenous metabolite, involved in multiple inflammatory diseases, but its role in sepsis-induced vascular injury remains unclear. The current study investigates the effect of 4-octyl itaconate (4-OI), a cell-permeable derivative of itaconic acid, on sepsis-induced vascular injury and organ damage. Methods and results An in vitro cell model was established by treating human umbilical vein endothelial cells (HUVECs) with lipopolysaccharide (LPS). Quantitative reverse transcription polymerase chain reaction (qRT-PCR) and enzyme-linked immunosorbent assay (ELISA) revealed that 4-OI inhibited the LPS-induced increases in TNF-α, IL-6, and IL-1β levels. Cellular reactive oxygen species (ROS) levels, measured using the fluorescent probe DCFH-DA, mitochondrial ROS (mtROS) levels, measured by MitoSOX, and mitochondrial membrane potential (ΔΨ), detected by the fluorescent indicator JC-1, were all reduced following 4-OI treatment. Additionally, mtDNA release, detected by qRT-PCR, were decreased. Mitochondrial morphology, assessed by PK Mito Orange, was preserved by 4-OI treatment. Furthermore, 4-OI suppressed HUVECs apoptosis and pyroptosis, as detected by TUNEL staining and western blotting. 4-OI treatment also significantly inhibited LPS-induced cell adhesion, as shown in THP-1 attachment assay, by decreasing ICAM-1 and VCAM-1 expression. Cell permeability, determined by FITC-Dx-70 leakage, revealed that 4-OI effectively suppressed LPS-induced increases in cell permeability. Furthermore, 4-OI inhibited LPS-induced phosphorylation and internalization of VE-cadherin protein, preserving the adhesion junctions between endothelial cells. Network pharmacology and molecular docking analysis suggested the involvement of TLR4/MAPK/NF-κB signaling pathway as a key mechanism by which 4-OI ameliorated sepsis-induced vascular cell inflammation and injury, which was confirmed by western blotting. The in vitro results were subsequently verified in vivo in an LPS-induced sepsis mouse model. 4-OI pretreatment substantially decreased inflammatory cytokine levels in serum and lung tissues, inhibited pulmonary oedema and pulmonary vascular leakage, as evidenced by the wet-to-dry weight ratio and Evans blue staining of lung tissues, and alleviated tissue damage, as shown by histological analysis. Survival analysis indicated that 4-OI post-sepsis treatment improved the overall survival rate in LPS-induced ALI mice. Conclusion 4-OI protects against sepsis-induced vascular injury and tissue damage by suppressing endothelial inflammation, oxidative stress, and preserving endothelial barrier integrity. Graphical abstract

Genetic line-specific immune profiles and immunometabolic responses to intramuscular lipopolysaccharide injection

2025-06-16

Kayla M. Elmore , Susan J. Lamont , Elizabeth Bobeck | Frontiers in Immunology

Previous research has investigated highly inbred chicken genetic lines from a metabolic, immune response, genetic profile, and immune trait standpoint, including response to lipopolysaccharide (LPS). Fayoumi lines (M5.1, M15.2) are … Previous research has investigated highly inbred chicken genetic lines from a metabolic, immune response, genetic profile, and immune trait standpoint, including response to lipopolysaccharide (LPS). Fayoumi lines (M5.1, M15.2) are known for their resistance to bacterial and viral infections, while Leghorn lines (Ghs6, Ghs13) display lower disease resistance. Results highlighted a need to increase LPS dose above initial work using 1mg/kg bodyweight (BW). Therefore, this study investigated the immune profiles and metabolic phenotypes of peripheral blood mononuclear cells (PBMC) from highly inbred genetic lines under resting and stressed metabolic states. Fifty-four adult birds from 5 highly inbred genetic lines (M5.1, M15.2, Ghs13, Line-8, and Sp-21.1) were randomly assigned to 0.9% sterile saline control or 2.4 mg/kg BW intramuscular LPS ( Escherichia coli O55:B5). BW was recorded at baseline before injection and 24 h post-injection (hpi). Cloacal temperature was recorded at baseline, 2 hpi, and 24 hpi, while blood was collected for flow cytometry and metabolic analysis. Data were analyzed using the SAS 9.4 MIXED procedure with genetic line, injection status, and interaction as fixed effects, with significance at p ≤ 0.05. Baseline immune cell profiles varied by line ( p ≤ 0.001). At 2 hpi, LPS did not impact BW or temperature, but influenced all queried immune cell populations while decreasing ATP production and glycolytic rates ( p ≤ 0.02). At 2 hpi, M5.1, Line-8, and Sp-21.1 LPS-inoculated birds had increased circulating CD3 + cells (51.8-62.3%, p ≤ 0.0001). LPS decreased CD3 + CD1.1 + cell levels by 34.1% at 2 hpi ( p ≤ 0.0001). M5.1, M15.2, and Line-8 controls had 14.9-66.5% higher CD3 + CD4 + levels than LPS-inoculated birds, while CD3 + CD4 + cells were 12.2% lower in Ghs13 post-LPS ( p ≤ 0.0001). CD3 + CD8α + populations increased 41.1-63.2% in all LPS-injected birds at 2 hpi, except Ghs13 ( p ≤ 0.0001). These results highlight genetic line-specific immune responses to LPS. By 24 hpi, immune profiles and glycolytic rates were largely recovered from LPS, while genetic line effects persisted, indicating line-specific immune responses ( p ≤ 0.04). Further understanding cellular preference and metabolic switching during inflammatory challenges could provide insight into how to best support and optimize bird performance during the production cycles.

Ovarian Cancer Drives TLR5-Dependent Expansion of Myeloid Progenitors Through Systemic Dissemination of Ligands

2025-06-15

Sree H. Kolli , Mitchell T. McGinty , Audrey M. Putelo +7 more | bioRxiv (Cold Spring Harbor Laboratory)

Ovarian cancer remains the most lethal gynecologic malignancy, due in part to the establishment of a profoundly immunosuppressive tumor microenvironment (TME). While TLR5 signaling has previously been implicated in promoting … Ovarian cancer remains the most lethal gynecologic malignancy, due in part to the establishment of a profoundly immunosuppressive tumor microenvironment (TME). While TLR5 signaling has previously been implicated in promoting myeloid cell recruitment to the ovarian TME, the upstream source of ligand and its systemic effects on hematopoiesis remain poorly understood(1,2). Here, we show that ovarian cancer disrupts gut barrier integrity, leading to systemic translocation of TLR5 ligands into the peritoneum, blood, and bone marrow. This translocation correlates with enhanced expansion of myeloid progenitors in the bone marrow of wild-type (WT) but not TLR5-deficient (TLR5 KO) mice, leading to enhanced accumulation of monocytes into the tumor microenvironment. Pharmacologic blockade of TLR5 in tumor-bearing mice alters the composition of tumor-associated myeloid populations, increasing the frequency of monocytes and CCR2-expressing macrophages In the bone marrow of tumor-bearing WT mice. In the bone marrow, blockade of TLR5 signaling led to expansion of granulocyte-monocyte progenitors (GMPs), a phenotype recapitulated in a competitive chimera model. In vitro, stimulation of WT bone marrow cells with purified TLR5 ligands led to enhanced colony formation and skewed differentiation toward granulocyte-macrophage lineages. These data reveal that chronic TLR5 signaling, driven by tumor-induced gut leakage, promotes expansion of myeloid cells within the bone marrow and is a host-intrinsic mechanism driving accumulation of immature monocytes and macrophages into the tumor microenvironment.

IL-1b-Bearing NETs: Bridging Inflammation to Early Cirrhosis in Hepatitis B

2025-06-15

Maria Ntinopoulou , Theocharis Konstantinidis , Anna Chalkidou +4 more | International Journal of Molecular Sciences

Hepatitis B virus (HBV) infection is one of the most dangerous viral diseases, with innate immunity representing the first line of defense against the virus. In this branch of the … Hepatitis B virus (HBV) infection is one of the most dangerous viral diseases, with innate immunity representing the first line of defense against the virus. In this branch of the immune system, neutrophils are considered key cellular mediators. To better understand the implication of neutrophils in the distinct stages of the disease, HBV-infected patients were enrolled in this study and categorized into three groups: patients with acute infection, chronic infection under treatment, and at early cirrhotic stage. To elucidate the role of inflammatory mediators and cellular mechanisms of neutrophilic origin in the course of the infection, both ex vivo and in vitro studies were performed. Increased levels of C-C motif chemokine ligand 2 (CCL2), interleukin (IL)-18, IL-33, and citrullinated histone H3 (CitH3)-an accurate marker of neutrophil extracellular traps (NETs)-were detected in the circulation of patients with acute infection or early cirrhosis. In parallel, sera from the aforementioned patient groups induced the formation of IL-1b-bearing NETs in neutrophils from healthy individuals. These inflammatory NETs affected primary fibroblasts towards acquiring a pro-fibrotic phenotype. These results suggest that NETs could be regarded as mediators in hepatitis B manifestations, while their therapeutic targeting could enhance the management of early-stage cirrhotic patients.

Bladder p75NTR-Mediated Anti-Inflammatory Response via the TLR4/TRAF6/NF-κB Axis

2025-06-14

Claudia Covarrubias , Abubakr H. Mossa , Laura R. Yan +4 more | Life

Recurrent bacterial cystitis in women can lead to interstitial cystitis or bladder pain syndrome (IC/BPS). Activation of Toll-like receptor 4 (TLR4) by LPS can upregulate signaling of the pro-inflammatory receptor … Recurrent bacterial cystitis in women can lead to interstitial cystitis or bladder pain syndrome (IC/BPS). Activation of Toll-like receptor 4 (TLR4) by LPS can upregulate signaling of the pro-inflammatory receptor p75NTR. The aim of the presented study was to assess whether p75NTR antagonist THX-B can modulate LPS-mediated inflammation in bladder cells. In vitro expression and LPS-activation of p75NTR were confirmed in urothelial (URO) and smooth muscle (SMC) cells. In UROs, p75NTR antagonism abolished the LPS-elicited rise in membrane-bound and soluble TNF-α. However, it could not prevent LPS-induced rise in phosphorylated ERK nor decrease in phosphorylated p38MAPK, nor the increase in iNOS and nitric oxide (NO) content. On the other hand, in SMCs, LPS increased phosphorylation of JNK, nuclear translocation of NF-κB, and association of TRAF6 to p75NTR, outcomes prevented by p75NTR antagonism. In UROs, LPS decreased the expression of tight junction proteins, ZO-1 and occludin, with the latter rescued by p75NTR antagonism. Intraurethral instillation of LPS increased inflammation in the lamina propria, activation of JNK, and contractile activity of bladder tissue. Alternatively, intraperitoneal THX-B injections prevented LPS-induced inflammation but not enhanced muscle contraction. Our results suggest that inhibition of p75NTR could help in reducing bladder symptoms during cystitis.

Emerging trends and focus of Toll-like receptors in kidney diseases: a 20-year bibliometric analysis

2025-06-13

P. Liu , Xinyao Luo , Dingyuan Wan +2 more | Frontiers in Medicine

Background An increasing number of studies have explored the role of Toll-like receptors (TLRs) in the pathogenesis of kidney diseases and their corresponding therapeutic potential. However, there is no comprehensive … Background An increasing number of studies have explored the role of Toll-like receptors (TLRs) in the pathogenesis of kidney diseases and their corresponding therapeutic potential. However, there is no comprehensive bibliometric analysis in this field. This study aims to investigate the hotspots and evolution of TLRs and kidney disease research over the past two decades. Methods Publications from the Web of Science Core Collection database were searched and extracted on December 21, 2024 using the terms “Toll-like receptor” and “kidney disease” (and their synonyms in MeSH). CiteSpace was used to explore publications from January 1, 2000, to December 21, 2024, to visualize the contributions of countries, institutions, journals, and authors, and to detect the evolution of research focus and emerging trends in this field. Results A total of 2,505 studies with 101,150 references were included in this study. The United States and China are the leading forces among all countries. The Egyptian Knowledge Bank is the leading institution, and Hans-Joachim Anders is considered the most influential expert in this field. PLOS One is the journal with the most publications, and Journal of Immunology is the most co-cited journal. According to the co-citation analysis, COVID-19 is the latest research hotspot. Additionally, both ischemia-reperfusion injury and diabetic nephropathy have been long-standing research hotspots and still hold significant values. Moreover, the use of TLR inhibitors as a therapeutic strategy for kidney diseases is increasingly emphasized. Conclusion Our study demonstrates a growing understanding of the crucial role of TLRs in kidney diseases over the past two decades. Future research should attach more importance to the identification of novel endogenous ligands for TLRs, which will be critical for developing TLR inhibitors as a viable therapeutic strategy.

IL-6 Induces CD45 Expression on Myeloid Cells

2025-06-13

Maryam Ahmed Al Barashdi , Ahlam Ali , Mary Frances McMullin +1 more | Sultan Qaboos University medical journal

1844-P: Cytokines Function to Mediate an Innate Immune/Endocrine Axis

2025-06-13

JACOB BARTOSIAK , KATHERINE HARTY , E. Schumacher +2 more | Diabetes

Introduction and Objective: It has been suggested that infection may contribute to T1D development via extended exposure of islets to proinflammatory cytokines. Recent evidence, however, suggests that the primary effects … Introduction and Objective: It has been suggested that infection may contribute to T1D development via extended exposure of islets to proinflammatory cytokines. Recent evidence, however, suggests that the primary effects of cytokine signaling in islets may be protective through the upregulation of antipathogen and antioxidant genes in β-cells. This study tests the hypothesis that there is an immune and endocrine axis in which endogenously produced cytokines function to initiate physiological islet responses and enhance β-cell fitness. Methods: Low dose (0.33 mg/kg) LPS was administered by IP injection to C57BL/6J mice. Serum cytokines were measured, and islets were isolated 3-24h later. Gene expression was evaluated in islet sub-populations using scRNA-seq with Seurat analysis and confirmed in islets by qRT-PCR. Protein expression was evaluated by immunofluorescent imaging of pancreatic sections. Results: Low dose LPS administration in mice stimulates the transient production of proinflammatory cytokines such as IL-1β that peak in the serum within 4-8h. Antipathogen genes are among the most highly upregulated genes in β-cells isolated from mice 6h after LPS-initiated immune stimulation as assessed by scRNA-seq. qRT-PCR of islets isolated from these animals show expression of these genes peaks within 3-6h of LPS administration and immunofluorescent imaging shows upregulation of protein expression for several representative antiviral genes. Additionally, β-cell identity genes are repressed within 6h of LPS administration. By 24h post-LPS administration, both antipathogen and islet identity gene expression return to baseline. Using LPS administration in mice with β-cell-specific deletion of the interleukin-1 type 1 signaling receptor (Il1r1), we’ve identified IL-1 as a key mediator of early β-cell responses to immune stimulation in vivo. Conclusion: These studies define a new model for studying the connection between the immune and endocrine systems and support our hypothesis that this interaction functions to enhance the fitness of islet endocrine cells. Disclosure J. Bartosiak: None. K. Harty: None. E. Schumacher: None. P. Hansen: None. J.A. Corbett: None. Funding National Institutes of Health (AI2212769)

Genomic Locus Tagged by Lung Function <scp>GWAS SNV</scp> rs12477314 (2q37.3) Acts as a Regulatory Region for a Systemic Inflammatory Phenotype

2025-06-13

Godwin M. Grech , Katherine A. Fawcett , Robert J. Hall +4 more | The FASEB Journal

ABSTRACT SNV rs12477314 (C>T; 1000G MAF = 0.14), which maps to an intergenic region on 2q37.3, is a genome‐wide significant association signal for pulmonary function in genome‐wide association study meta‐analyses. … ABSTRACT SNV rs12477314 (C>T; 1000G MAF = 0.14), which maps to an intergenic region on 2q37.3, is a genome‐wide significant association signal for pulmonary function in genome‐wide association study meta‐analyses. Bioinformatic analysis revealed that the intergenic region in proximity to the sentinel SNV is enriched for histone methylation markers suggestive of active enhancer regions modifiable by DNA methylation. The aim of this study was to investigate the functionality of putative enhancer/s and their potential interaction with CpG islands in the genomic region tagged by rs12477314 and their relevance to lung disease, in particular COPD. Two independent CRISPR/Cas9n‐targeted deletions of the putative enhancer/s were performed in an airway epithelial cell line (NCI‐H460). Deletion clones were subjected to RNA‐Seq, and differential expression gene (DEG) datasets were generated using the Cufflinks version 2.2.1 pipeline ( p‐ FDR < 0.05). Biological pathway analysis was performed using Qiagen's Ingenuity Pathway Analysis. Associations with the blood proteome were explored in UK Biobank. Our results suggest that the deleted regions are co‐acting enhancers regulating overlapping gene expression patterns. The DEG datasets from the two genomic deletions are enriched for similar canonical pathways, which may contribute to a pro‐inflammatory phenotype. Pathway‐based regulatory effects analysis of the two DEG datasets resulted in identifying potential downstream biological processes. There was overlap between the pathways identified in protein association datasets and the DEG datasets. Our results suggest that the genomic region tagged by SNV rs12477314 constitutes a regulatory region responsible for regulating biological pathways conducive to a systemic inflammatory phenotype.

c-di-GMP does not bind H-NS, nor inhibits H-NS binding DNA

2025-06-12

Jiayu Wang , Hengxi Wei , Bin Xia | Nature Communications

Immunomodulatory effects of 4-hydroxynonenal

2025-06-06

Melina Ioannidis , Johanna Tjepkema , Michael R P Uitbeijerse +1 more | Redox Biology

The reactive aldehyde 4-hydroxy-2-nonenal (4-HNE) is a byproduct of lipid peroxidation driven by reactive oxygen species (ROS). 4-HNE covalently binds to macromolecules such as proteins, altering their functions. While 4-HNE … The reactive aldehyde 4-hydroxy-2-nonenal (4-HNE) is a byproduct of lipid peroxidation driven by reactive oxygen species (ROS). 4-HNE covalently binds to macromolecules such as proteins, altering their functions. While 4-HNE is implicated in various ROS-related pathologies, its impact on the immune system remains incompletely understood. This review explores how 4-HNE influences molecular mechanisms involved in inflammation and immune cell functions. 4-HNE modulates inflammation through the interaction with several signaling pathways, including nuclear factor kappa-light-chain enhancement of activated B cells (NF-κB), nuclear factor erythroid 2-related factor (Nrf2), mitogen-activated protein kinases (MAPK), toll-like receptor (TLR) 4, and stimulator of interferon genes (STING), thereby affecting immune responses and modulating cytokine production and inflammasome activation. However, its effects are complex, exhibiting both pro- and anti-inflammatory properties depending on dose and cell type. This review highlights the multiple mechanisms by which 4-HNE modulates the immune cells' responses.

Partial depletion of circulating neutrophil granulocytes in mice exacerbates the inflammatory response and hypothermia during LPS induced severe systemic inflammation

2025-06-04

Jessica Hernandez‐Rodriguez , Fabian Johannes Pflieger , Julia Schäffer +7 more | Frontiers in Immunology

Introduction During acute inflammation, immune-to-brain signaling plays a pivotal role in the generation of sickness responses such as fever or hypothermia. Neutrophil granulocytes (NG) are a crucial component of the … Introduction During acute inflammation, immune-to-brain signaling plays a pivotal role in the generation of sickness responses such as fever or hypothermia. Neutrophil granulocytes (NG) are a crucial component of the immune system and modulate inflammation. Moreover, neutropenic fever is a severe condition for immunocompromised patients that can be life threatening. Using a mouse model of partial NG depletion, we aimed to investigate how neutropenia alters immune-to-brain signaling and the development of sickness responses during high-dose-LPS-induced inflammation. Methods To deplete NGs, mice were injected intraperitoneally (IP) with heterologous anti-polymorphonuclear leukocyte serum at 1:4 ratio in PBS (PMN, 1.82 mg/kg IgG) or normal rabbit serum (NRS, 1 mg/kg IgG) as a control. To induce inflammation, mice were injected IP with lipopolysaccharide (LPS, 2.5 mg/kg) or PBS as a control 24 h after PMN or NRS. Physiological parameters were documented using a telemetric system that continuously recorded: food and water intake, locomotor activity, and core body temperature. At 4 h or 24 h after LPS-stimulation, brain and serum samples were collected and analyzed for peripheral and brain inflammatory markers. Results After stimulation with LPS, PMN-pretreated mice showed neutropenia (significantly by ~25% of the control value) and attenuated NG recruitment to the brain in a structure dependent manner. LPS-induced hypothermia was more severe in PMN-pretreated mice while other physiological parameters were only altered by LPS alone. Additional analyses in NG depleted mice revealed that corticosterone levels showed an early reduced but late increased magnitude, and circulating cytokines like interleukin-10 were exacerbated during LPS-induced inflammation. Despite a weak overall impact on the brain, the hypothalamus of neutropenic mice presented exacerbated LPS-induced levels of IL-6, a key mediator of inflammation, compared to immunocompetent control mice. Discussion Overall, we found that partial NG depletion exaggerates the peripheral inflammatory response and this strong peripheral reaction may contribute to the exacerbation of sickness symptoms most likely involving circulating IL-10 with strong implications for clinical cases of neutropenic patients.