BACKGROUND: The two forms of human inflammatory bowel disease, Crohn's disease (CD) and ulcerative colitis (UC), are both associated with loss of tolerance to gut microbial antigens. The dominant antigen recognized by antibody and T-cell responses in patients with CD is bacterial flagellin. Flagellin is also the only known ligand for Toll-like receptor 5 (TLR5), a key protein in innate immunity. Although flagellin activates TLR5 to produce inflammatory responses in many cell types in the gut, there is conflicting evidence as to whether TLR5 is harmful or protective in CD and murine colitis models. A recent study found that administration of flagellin enemas to mice along with dextran sodium sulfate (DSS) made their colitis worse. METHODS: We sought to determine whether this exacerbation was due to TLR5 ligation, or to TLR5-independent adaptive immune responses to flagellin as an antigen, by using a transposon insertional mutant of the Escherichia coli H18 flagellin, 2H3, which lacks TLR5 stimulatory activity. RESULTS: We found that flagellin enemas produced only a mild exacerbation of DSS colitis, and that 2H3 was equivalent to or worse than wildtype flagellin. Moreover, we found that DSS colitis was more severe in TLR5(-/-) mice than wildtype C57BL/6 mice. CONCLUSIONS: Together, these results suggest that flagellin-mediated exacerbation of colitis is independent of TLR5.
BACKGROUND: The two forms of humaninflammatory bowel disease, Crohn's disease (CD) and ulcerative colitis (UC), are both associated with loss of tolerance to gut microbial antigens. The dominant antigen recognized by antibody and T-cell responses in patients with CD is bacterial flagellin. Flagellin is also the only known ligand for Toll-like receptor 5 (TLR5), a key protein in innate immunity. Although flagellin activates TLR5 to produce inflammatory responses in many cell types in the gut, there is conflicting evidence as to whether TLR5 is harmful or protective in CD and murinecolitis models. A recent study found that administration of flagellin enemas to mice along with dextran sodium sulfate (DSS) made their colitis worse. METHODS: We sought to determine whether this exacerbation was due to TLR5 ligation, or to TLR5-independent adaptive immune responses to flagellin as an antigen, by using a transposon insertional mutant of the Escherichia coli H18 flagellin, 2H3, which lacks TLR5 stimulatory activity. RESULTS: We found that flagellin enemas produced only a mild exacerbation of DSS colitis, and that 2H3 was equivalent to or worse than wildtype flagellin. Moreover, we found that DSS colitis was more severe in TLR5(-/-) mice than wildtype C57BL/6 mice. CONCLUSIONS: Together, these results suggest that flagellin-mediated exacerbation of colitis is independent of TLR5.
Authors: Sybille Kenzel; Miriam Mergen; Julius von Süßkind-Schwendi; Julia Wennekamp; Sachin D Deshmukh; Monika Haeffner; Antigoni Triantafyllopoulou; Sebastian Fuchs; Susan Farmand; Sandra Santos-Sierra; Jochen Seufert; Timo K van den Berg; Taco W Kuijpers; Philipp Henneke Journal: J Immunol Date: 2012-09-26 Impact factor: 5.422
Authors: Konrad Aden; Ateequr Rehman; Maren Falk-Paulsen; Thomas Secher; Jan Kuiper; Florian Tran; Steffen Pfeuffer; Raheleh Sheibani-Tezerji; Alexandra Breuer; Anne Luzius; Marlene Jentzsch; Robert Häsler; Susanne Billmann-Born; Olga Will; Simone Lipinski; Richa Bharti; Timon Adolph; Juan L Iovanna; Sarah L Kempster; Richard S Blumberg; Stefan Schreiber; Burkhard Becher; Mathias Chamaillard; Arthur Kaser; Philip Rosenstiel Journal: Cell Rep Date: 2016-08-11 Impact factor: 9.423
Authors: Jared Sheridan; David R Mack; Devendra K Amre; David M Israel; Artem Cherkasov; Huifang Li; Guy Grimard; Theodore S Steiner Journal: PLoS One Date: 2013-04-11 Impact factor: 3.240