TLR5 is not required for flagellin-mediated exacerbation of DSS colitis.
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.
Ivison
Sabine M
SM
Division of Infectious Diseases, Department of Medicine, University of British Columbia, Vancouver, BC, Canada.
Himmel
Megan E
ME
Hardenberg
Gijs
G
Wark
Paige A J
PA
Kifayet
Arnawaz
A
Levings
Megan K
MK
Steiner
Theodore S
TS
D000818:Animals; D000907:Antibodies, Bacterial / Q000097:blood; D003092:Colitis / Q000139:chemically induced* / Q000276:immunology* / Q000401:mortality; D004251:DNA Transposable Elements; D016264:Dextran Sulfate / Q000633:toxicity; D004733:Enema; D004926:Escherichia coli / Q000235:genetics; D005408:Flagellin / Q000235:genetics / Q000276:immunology* / Q000494:pharmacology; D006367:HeLa Cells; D006801:Humans; D007074:Immunoglobulin G / Q000378:metabolism; D018664:Interleukin-12 / Q000378:metabolism; D007413:Intestinal Mucosa / Q000276:immunology / Q000378:metabolism; D008297:Male; D051379:Mice; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D012486:Salmonella typhimurium / Q000235:genetics; D051198:Toll-Like Receptor 5 / Q000235:genetics / Q000276:immunology* / Q000378:metabolism*; D015431:Weight Loss
D000907:Antibodies, Bacterial; D004251:DNA Transposable Elements; D007074:Immunoglobulin G; D051198:Toll-Like Receptor 5; D005408:Flagellin; D018664:Interleukin-12; D016264:Dextran Sulfate