TLR5 Signaling in the Regulation of Intestinal Mucosal Immunity

Abstract Toll-like receptor 5 (TLR5) is a pattern recognition receptor that specifically recognizes flagellin and consequently plays a crucial role in the control of intestinal homeostasis by activating innate and adaptive immune responses. TLR5 overexpression, on the other hand, might disrupt the intestinal mucosal barrier, which serves as the first line of defense against harmful microbes. The intestine symbiotic bacteria, mucous layer, intestinal epithelial cells (IECs), adherens junctions (such as tight junctions and peripheral membrane proteins), the intestinal mucosal immune system, and cytokines make up the intestinal mucosal barrier. Impaired barrier function has been linked to intestinal illnesses such as inflammatory bowel disease (IBD). IBD is a persistent non-specific inflammatory illness of the digestive system with an unknown cause. It is now thought to be linked to infection, environment, genes, immune system, and the gut microbiota. The significance of immunological dysfunction in IBD has received more attention in recent years. The purpose of this paper is to explore TLR5’s position in the intestinal mucosal barrier and its relevance to IBD.

[1]  R. Gazzinelli,et al.  Regulation of innate immune signaling by IRAK proteins , 2023, Frontiers in Immunology.

[2]  S. Scheurer,et al.  The Flagellin:Allergen Fusion Protein rFlaA:Betv1 Induces a MyD88− and MAPK-Dependent Activation of Glucose Metabolism in Macrophages , 2021, Cells.

[3]  M. Rosenkilde,et al.  Dendritic Cells and CCR7 Expression: An Important Factor for Autoimmune Diseases, Chronic Inflammation, and Cancer , 2021, International journal of molecular sciences.

[4]  D. Reed,et al.  Cellular context of IL-33 expression dictates impact on anti-helminth immunity , 2020, Science Immunology.

[5]  T. Tochio,et al.  Intestinal microbiota transplantation reveals the role of microbiota in dietary regulation of RegIIIβ and RegIIIγ expression in mouse intestine. , 2020, Biochemical and biophysical research communications.

[6]  Wen Zhang,et al.  Toll-like receptor 5-mediated signaling enhances liver regeneration in mice , 2020, Military Medical Research.

[7]  Zhi Wei,et al.  Paneth Cell-Derived Lysozyme Defines the Composition of Mucolytic Microbiota and the Inflammatory Tone of the Intestine. , 2020, Immunity.

[8]  S. Acton,et al.  Molecular mechanisms of dendritic cell migration in immunity and cancer , 2020, Medical Microbiology and Immunology.

[9]  K. Hilligan,et al.  Antigen presentation by dendritic cells and their instruction of CD4+ T helper cell responses , 2020, Cellular & Molecular Immunology.

[10]  K. Fitzgerald,et al.  Toll-like Receptors and the Control of Immunity , 2020, Cell.

[11]  R. Newberry,et al.  In vivo labeling of epithelial cell–associated antigen passages in the murine intestine , 2020, Lab Animal.

[12]  S. Targan,et al.  Development of Physiologically Responsive Human iPSC-Derived Intestinal Epithelium to Study Barrier Dysfunction in IBD , 2020, International journal of molecular sciences.

[13]  C. Hsieh,et al.  Goblet Cell Associated Antigen Passages Support the Induction and Maintenance of Oral Tolerance , 2019, Mucosal Immunology.

[14]  D. Mccole,et al.  The JAK-Inhibitor Tofacitinib Rescues Human Intestinal Epithelial Cells and Colonoids from Cytokine-Induced Barrier Dysfunction. , 2019, Inflammatory bowel diseases.

[15]  Yu-hong Yuan,et al.  NEK7 interacts with NLRP3 to modulate the pyroptosis in inflammatory bowel disease via NF-κB signaling , 2019, Cell Death & Disease.

[16]  T. Hielscher,et al.  Asymmetric distribution of TLR3 leads to a polarized immune response in human intestinal epithelial cells , 2019, Nature Microbiology.

[17]  I. Williams,et al.  Intestinal M cells: Tireless samplers of enteric microbiota , 2019, Traffic.

[18]  Nupur K. Das,et al.  Intestinal non-canonical NFκB signaling shapes the local and systemic immune response , 2019, Nature Communications.

[19]  Yuting He,et al.  TLR5 silencing reduced hyperammonaemia-induced liver injury by inhibiting oxidative stress and inflammation responses via inactivating NF-κB and MAPK signals. , 2019, Chemico-biological interactions.

[20]  Katherine R. Balka,et al.  Understanding early TLR signaling through the Myddosome , 2018, Journal of leukocyte biology.

[21]  S. Kimura,et al.  M cell-dependent antigen uptake on follicle-associated epithelium for mucosal immune surveillance , 2018, Inflammation and regeneration.

[22]  H. Tilg,et al.  Paneth Cells and their Antimicrobials in Intestinal Immunity. , 2018, Current pharmaceutical design.

[23]  L. Tordesillas,et al.  Mechanisms of Oral Tolerance , 2018, Clinical Reviews in Allergy & Immunology.

[24]  H. Hug,et al.  Toll-Like Receptors: Regulators of the Immune Response in the Human Gut , 2018, Nutrients.

[25]  Mark J. Miller,et al.  Goblet Cell Associated Antigen Passages are Inhibited During Salmonella typhimurium Infection to Prevent Pathogen Dissemination and Limit Responses to Dietary Antigens , 2018, Mucosal Immunology.

[26]  H. Wilson,et al.  Recognizing conserved non-canonical localization patterns of toll-like receptors in tissues and across species , 2018, Cell and Tissue Research.

[27]  P. Vogel,et al.  Pyrin Inflammasome Regulates Tight Junction Integrity to Restrict Colitis and Tumorigenesis. , 2017, Gastroenterology.

[28]  J. Sirard,et al.  Compartmentalized Antimicrobial Defenses in Response to Flagellin. , 2017, Trends in microbiology.

[29]  T. Phan,et al.  Impaired Intestinal Permeability Contributes to Ongoing Bowel Symptoms in Patients With Inflammatory Bowel Disease and Mucosal Healing. , 2017, Gastroenterology.

[30]  L. Arike,et al.  Intestinal Muc2 mucin O-glycosylation is affected by microbiota and regulated by differential expression of glycosyltranferases , 2017, Glycobiology.

[31]  Minhu Chen,et al.  Upregulation of miR-665 promotes apoptosis and colitis in inflammatory bowel disease by repressing the endoplasmic reticulum stress components XBP1 and ORMDL3 , 2017, Cell Death & Disease.

[32]  L. Lopetuso,et al.  Epithelial-specific Toll-like Receptor (TLR)5 Activation Mediates Barrier Dysfunction in Experimental Ileitis , 2017, Inflammatory bowel diseases.

[33]  A. Waisman,et al.  Dendritic cells as gatekeepers of tolerance , 2016, Seminars in Immunopathology.

[34]  Sung-il Yoon,et al.  A conserved TLR5 binding and activation hot spot on flagellin , 2017, Scientific Reports.

[35]  Yingwei Chen,et al.  Inhibition of Autophagic Degradation Process Contributes to Claudin-2 Expression Increase and Epithelial Tight Junction Dysfunction in TNF-α Treated Cell Monolayers , 2017, International journal of molecular sciences.

[36]  M. Balda,et al.  Tight junctions: from simple barriers to multifunctional molecular gates , 2016, Nature Reviews Molecular Cell Biology.

[37]  M. Johansson,et al.  A sentinel goblet cell guards the colonic crypt by triggering Nlrp6-dependent Muc2 secretion , 2016, Science.

[38]  C. Huttenhower,et al.  Paneth cell defects in Crohn's disease patients promote dysbiosis. , 2016, JCI insight.

[39]  Han Liu,et al.  TLR5 mediates CD172α+ intestinal lamina propria dendritic cell induction of Th17 cells , 2016, Scientific Reports.

[40]  I. Williams,et al.  Antigen sampling by intestinal M cells is the principal pathway initiating mucosal IgA production to commensal enteric bacteria , 2015, Mucosal Immunology.

[41]  M. Sun,et al.  Regulatory immune cells in regulation of intestinal inflammatory response to microbiota , 2015, Mucosal Immunology.

[42]  Shiyan Yu,et al.  Compartmentalizing intestinal epithelial cell toll-like receptors for immune surveillance , 2015, Cellular and Molecular Life Sciences.

[43]  G. Gambassi,et al.  How the Intricate Interaction among Toll-Like Receptors, Microbiota, and Intestinal Immunity Can Influence Gastrointestinal Pathology , 2015, Journal of immunology research.

[44]  R. Ley,et al.  Intestinal epithelial cell toll-like receptor 5 regulates the intestinal microbiota to prevent low-grade inflammation and metabolic syndrome in mice. , 2014, Gastroenterology.

[45]  Martyn F. Symmons,et al.  Assembly and localization of Toll-like receptor signalling complexes , 2014, Nature Reviews Immunology.

[46]  M. Gao,et al.  Interleukin-8 Regulates Endothelial Permeability by Down-regulation of Tight Junction but not Dependent on Integrins Induced Focal Adhesions , 2013, International journal of biological sciences.

[47]  S. Ng,et al.  First Prospective, Population-Based Inflammatory Bowel Disease Incidence Study in Mainland of China: The Emergence of “Western” Disease , 2013, Inflammatory bowel diseases.

[48]  Omry Koren,et al.  AIEC pathobiont instigates chronic colitis in susceptible hosts by altering microbiota composition , 2013, Gut.

[49]  S. Ng,et al.  Incidence and phenotype of inflammatory bowel disease based on results from the Asia-pacific Crohn's and colitis epidemiology study. , 2013, Gastroenterology.

[50]  Helen Y Wang,et al.  Cell type-specific function of TAK1 in innate immune signaling. , 2013, Trends in immunology.

[51]  Mark J. Miller,et al.  Transepithelial antigen delivery in the small intestine: different paths, different outcomes , 2013, Current opinion in gastroenterology.

[52]  F. Powrie,et al.  CD4+ T-cell subsets in intestinal inflammation , 2013, Immunological reviews.

[53]  H. Clevers,et al.  Paneth cells: maestros of the small intestinal crypts. , 2013, Annual review of physiology.

[54]  William A. Walters,et al.  Transient inability to manage proteobacteria promotes chronic gut inflammation in TLR5-deficient mice. , 2012, Cell host & microbe.

[55]  C. Elson,et al.  Regulation of Toll-like Receptor 5 Gene Expression and Function on Mucosal Dendritic Cells , 2012, PloS one.

[56]  T. Hohl,et al.  Interleukin 23 production by intestinal CD103(+)CD11b(+) dendritic cells in response to bacterial flagellin enhances mucosal innate immune defense. , 2012, Immunity.

[57]  N. Shroyer,et al.  Intestinal development and differentiation. , 2011, Experimental cell research.

[58]  R. Seger,et al.  The MAPK cascades: signaling components, nuclear roles and mechanisms of nuclear translocation. , 2011, Biochimica et biophysica acta.

[59]  S. Halle,et al.  Afferent lymph–derived T cells and DCs use different chemokine receptor CCR7–dependent routes for entry into the lymph node and intranodal migration , 2011, Nature Immunology.

[60]  K. Ishii,et al.  A New Subset of CD103+CD8α+ Dendritic Cells in the Small Intestine Expresses TLR3, TLR7, and TLR9 and Induces Th1 Response and CTL Activity , 2011, The Journal of Immunology.

[61]  J. Samsom,et al.  Adaptive T‐cell responses regulating oral tolerance to protein antigen , 2011, Allergy.

[62]  Y. Belkaid,et al.  Essential role for retinoic acid in the promotion of CD4(+) T cell effector responses via retinoic acid receptor alpha. , 2011, Immunity.

[63]  S. Akira,et al.  TLR5 functions as an endocytic receptor to enhance flagellin‐specific adaptive immunity , 2011, European journal of immunology.

[64]  A. Ouellette.  Paneth cells and innate mucosal immunity , 2010, Current opinion in gastroenterology.

[65]  S. Barratt-Boyes,et al.  Enemy at the gates: dendritic cells and immunity to mucosal pathogens , 2010, Cell Research.

[66]  Gunnar C. Hansson,et al.  The two mucus layers of colon are organized by the MUC2 mucin, whereas the outer layer is a legislator of host–microbial interactions , 2010, Proceedings of the National Academy of Sciences.

[67]  Richard A Flavell,et al.  Bacterial flagellin stimulates Toll-like receptor 5-dependent defense against vancomycin-resistant Enterococcus infection. , 2010, The Journal of infectious diseases.

[68]  Maria T. Abreu,et al.  Toll-like receptor signalling in the intestinal epithelium: how bacterial recognition shapes intestinal function , 2010, Nature Reviews Immunology.

[69]  N. Ishimura,et al.  A20 is an early responding negative regulator of Toll‐like receptor 5 signalling in intestinal epithelial cells during inflammation , 2010, Clinical and experimental immunology.

[70]  A. Schäffer,et al.  Inflammatory bowel disease and mutations affecting the interleukin-10 receptor. , 2009, The New England journal of medicine.

[71]  P. Wierzbicki,et al.  Decreased Toll-like receptor-5 (TLR-5) expression in the mucosa of ulcerative colitis patients. , 2009, Journal of physiology and pharmacology : an official journal of the Polish Physiological Society.

[72]  A. Gewirtz,et al.  Role of flagellin in Crohn's disease: Emblematic of the progress and enigmas in understanding inflammatory bowel disease , 2009, Inflammatory bowel diseases.

[73]  L. Frulloni,et al.  Antiflagellin antibodies recognize the autoantigens Toll‐Like Receptor 5 and Pals 1‐associated tight junction protein and induce monocytes activation and increased intestinal permeability in Crohn’s disease , 2009, Journal of internal medicine.

[74]  Sarah L. Brown,et al.  A key role for autophagy and the autophagy gene Atg16l1 in mouse and human intestinal Paneth cells , 2008, Nature.

[75]  M. Dubinsky.  What is the role of serological markers in the diagnosis of IBD? , 2008, Inflammatory bowel diseases.

[76]  M. Neutra,et al.  Effects of flagellin on the functions of follicle-associated epithelium. , 2008, The Journal of infectious diseases.

[77]  Hiroshi Kiyono,et al.  Regulation of humoral and cellular gut immunity by lamina propria dendritic cells expressing Toll-like receptor 5 , 2008, Nature Immunology.

[78]  D. Philpott,et al.  The ubiquitin-editing enzyme A20 restricts nucleotide-binding oligomerization domain containing 2-triggered signals. , 2008, Immunity.

[79]  G. Plitas,et al.  MyD88-mediated signals induce the bactericidal lectin RegIIIγ and protect mice against intestinal Listeria monocytogenes infection , 2007, The Journal of experimental medicine.

[80]  J. Coombes,et al.  Control of intestinal homeostasis by regulatory T cells and dendritic cells. , 2007, Seminars in immunology.

[81]  Jun Sun,et al.  Flagellin-induced tolerance of the Toll-like receptor 5 signaling pathway in polarized intestinal epithelial cells. , 2007, American journal of physiology. Gastrointestinal and liver physiology.

[82]  Sankar Ghosh,et al.  Recognition and signaling by toll-like receptors. , 2006, Annual review of cell and developmental biology.

[83]  Judy H Cho,et al.  Dominant-negative TLR5 polymorphism reduces adaptive immune response to flagellin and negatively associates with Crohn's disease. , 2006, American journal of physiology. Gastrointestinal and liver physiology.

[84]  J. Sirard,et al.  Mucosal interplay among commensal and pathogenic bacteria: Lessons from flagellin and Toll‐like receptor 5 , 2006, FEBS letters.

[85]  S. Targan,et al.  Antibodies to CBir1 flagellin define a unique response that is associated independently with complicated Crohn's disease. , 2005, Gastroenterology.

[86]  Tatsuo Yamamoto,et al.  Anti-CD3 induces bi-phasic apoptosis in murine intestinal epithelial cells: possible involvement of the Fas/Fas ligand system in different T cell compartments. , 2005, International immunology.

[87]  J. Sirard,et al.  Bacterial flagellins: mediators of pathogenicity and host immune responses in mucosa. , 2004, Trends in microbiology.

[88]  J. Sirard,et al.  Dendritic cells: the host Achille's heel for mucosal pathogens? , 2004, Trends in microbiology.

[89]  A. Aderem,et al.  Toll-like receptor 5 recognizes a conserved site on flagellin required for protofilament formation and bacterial motility , 2003, Nature Immunology.

[90]  J. Madara,et al.  Flagellin Is the Major Proinflammatory Determinant of Enteropathogenic Salmonella1 , 2003, The Journal of Immunology.

[91]  M. Barančík,et al.  Mitogen-activated protein kinases and their role in regulation of cellular processes. , 2002, General physiology and biophysics.

[92]  P. Godowski,et al.  Cutting Edge: Bacterial Flagellin Activates Basolaterally Expressed TLR5 to Induce Epithelial Proinflammatory Gene Expression1 , 2001, The Journal of Immunology.

[93]  J. Stockman,et al.  Metabolic Syndrome and Altered Gut Microbiota in Mice Lacking Toll-Like Receptor 5 , 2012 .

[94]  Isabelle Cleynen,et al.  Resequencing of positional candidates identifies low frequency IL23R coding variants protecting against inflammatory bowel disease , 2011, Nature Genetics.

[95]  A. Gewirtz,et al.  Flagellin/TLR5 responses in epithelia reveal intertwined activation of inflammatory and apoptotic pathways. , 2006, American journal of physiology. Gastrointestinal and liver physiology.

[96]  S. Targan,et al.  Bacterial flagellin is a dominant antigen in Crohn disease. , 2004, The Journal of clinical investigation.