title: Pathophysiological role of Toll-like receptor 5 engagement by bacterial flagellin in colonic inflammation.
abstract: Commensal and enteroinvasive microbes in the human gut release bacterial flagellin, a specific microbial ligand of Toll-like receptor 5 (TLR5). However, the pathophysiological role of bacterial flagellin in gastrointestinal inflammation has not been determined. Here we evaluated the role of bacterial flagellin using native human colonic mucosa and the mouse colitis model of dextran sulfate sodium (DSS). We demonstrate that, in intact human colonic mucosa, the flagellin/TLR5 response occurs only after exposure to the basolateral, not the apical, surface, implying a basolaterally polarized TLR5 response in human colonic mucosa. In this context, flagellin exposure to injured colonic mucosa due to DSS administration in mice resulted in a TLR5-associated response evaluated by in vivo activation of mitogen-activated protein kinase/extracellular signal-related kinase 1/2 (MEK1/2) and elevated IL-6, TNF-alpha, and keratinocyte-derived chemokine production, whereas intact colonic mucosa did not respond to flagellin. Moreover, flagellin exposure to injured mouse colon in vivo, but not to intact colon, also significantly aggravated colonic inflammation, increased mouse mortality, and enhanced histopathological damage in the colonic mucosa. However, the TLR2-specific agonist, peptidoglycan or lipoteichoic acid, did not cause an inflammatory response in intact or DSS-injured mouse colon. Furthermore, intracolonic flagellin administration in mice causes severe apoptosis in colonic epithelium disrupted by DSS administration. These data suggest that intracolonic flagellin via TLR5 engagement is able to elicit inflammatory responses in disrupted colon, whereas the normal colon is not responsive to bacterial flagellin. These results demonstrate that bacterial flagellin plays an important role in the development and progress of colitis.
authors.affiliation: Division of Gastroenterology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA.
authors.forename: Sang Hoon
authors.initials: SH
authors.lastname: Rhee
authors.forename: Eunok
authors.initials: E
authors.lastname: Im
authors.forename: Martin
authors.initials: M
authors.lastname: Riegler
authors.forename: Efi
authors.initials: E
authors.lastname: Kokkotou
authors.forename: Michael
authors.initials: M
authors.lastname: O'brien
authors.forename: Charalabos
authors.initials: C
authors.lastname: Pothoulakis
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000276:immunology; D018925:Chemokines / Q000276:immunology; D003092:Colitis / Q000139:chemically induced / Q000276:immunology* / Q000473:pathology; D003106:Colon / Q000473:pathology / Q000503:physiopathology*; D005408:Flagellin / Q000276:immunology* / Q000494:pharmacology; D006801:Humans; D007249:Inflammation / Q000276:immunology / Q000473:pathology; D015850:Interleukin-6 / Q000276:immunology; D007413:Intestinal Mucosa / Q000276:immunology / Q000473:pathology; D015603:Keratinocytes / Q000276:immunology / Q000473:pathology; D008070:Lipopolysaccharides / Q000276:immunology / Q000494:pharmacology; D048369:MAP Kinase Kinase 1 / Q000276:immunology; D048370:MAP Kinase Kinase 2 / Q000276:immunology*; D008297:Male; D008562:Membrane Glycoproteins / Q000819:agonists / Q000276:immunology*; D051379:Mice; D010457:Peptidoglycan / Q000276:immunology / Q000494:pharmacology; D011956:Receptors, Cell Surface / Q000819:agonists / Q000276:immunology*; D015398:Signal Transduction / Q000187:drug effects / Q000276:immunology*; D013682:Teichoic Acids / Q000276:immunology / Q000494:pharmacology; D046509:Tissue Culture Techniques; D051195:Toll-Like Receptor 2; D051198:Toll-Like Receptor 5; D051193:Toll-Like Receptors; D014409:Tumor Necrosis Factor-alpha / Q000276:immunology
chemical_list: D018925:Chemokines; D015850:Interleukin-6; D008070:Lipopolysaccharides; D008562:Membrane Glycoproteins; D010457:Peptidoglycan; D011956:Receptors, Cell Surface; C495342:TLR2 protein, human; C495346:TLR5 protein, human; D013682:Teichoic Acids; D051195:Toll-Like Receptor 2; D051198:Toll-Like Receptor 5; D051193:Toll-Like Receptors; D014409:Tumor Necrosis Factor-alpha; D005408:Flagellin; C009900:lipoteichoic acid; D048369:MAP Kinase Kinase 1; D048370:MAP Kinase Kinase 2; C482127:Map2k1 protein, mouse; C482129:Map2k2 protein, mouse