Pathophysiological role of Toll-like receptor 5 engagement by bacterial flagellin in colonic inflammation

Rhee, Sang Hoon, Im, Eunok, Riegler, Martin, Kokkotou, Efi, O'Brien, Michael and Pothoulakis, Charalabos (2005) Pathophysiological role of Toll-like receptor 5 engagement by bacterial flagellin in colonic inflammation. Proceedings of The National Academy of Sciences of The United States of America, 102 38: 13610-13615. doi:10.1073/pnas.0502174102


Author Rhee, Sang Hoon
Im, Eunok
Riegler, Martin
Kokkotou, Efi
O'Brien, Michael
Pothoulakis, Charalabos
Title Pathophysiological role of Toll-like receptor 5 engagement by bacterial flagellin in colonic inflammation
Journal name Proceedings of The National Academy of Sciences of The United States of America   Check publisher's open access policy
ISSN 0027-8424
Publication date 2005-09-20
Sub-type Article (original research)
DOI 10.1073/pnas.0502174102
Open Access Status Not Open Access
Volume 102
Issue 38
Start page 13610
End page 13615
Total pages 6
Place of publication Washington D.C.
Publisher National Academy of Sciences of the U.S.
Language eng
Subject 06 Biological Sciences
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 f lagellin/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 kerati nocyte-cle rived 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, pepticloglycan 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.
Keyword Multidisciplinary Sciences
innate immunity
colitis
commensal bacteria
Toll-like Receptors
Intestinal Epithelial-cells
Bowel-disease
In-vitro
Gene-expression
Protein
Induce
Tlr5
Recognition
Macrophages
Q-Index Code C1
Q-Index Status Provisional Code
Institutional Status Unknown

Document type: Journal Article
Sub-type: Article (original research)
Collections: Excellence in Research Australia (ERA) - Collection
School of Biological Sciences Publications
 
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Created: Fri, 28 Mar 2008, 15:31:07 EST