TLR5 activation induces secretory interleukin-1 receptor antagonist (sIL-1Ra) and reduces inflammasome-associated tissue damage.
Toll-like receptor-5 (TLR5)-mediated detection of flagellin induces nuclear factor (NF)-κB-mediated transcription of host defense gene expression, whereas recognition of intracellular flagellin by interleukin (IL)-1-converting enzyme protease-activation factor (IPAF) results in maturation/secretion of the inflammasome cytokine IL-1β. The potent effects of IL-1β are counter-regulated by secretory IL-1 receptor antagonist (sIL-1Ra). We studied the roles of flagellin receptors in regulating the expression of IL-1β and sIL-1Ra and their subsequent roles in inflammation. Flagellin induced sIL-1Ra in intestinal epithelia and macrophages in a dose- and time-dependent manner, whereas IL-1β was only induced in macrophages. In vivo, flagellin-induced sIL-1Ra, but not IL-1β, was absolutely dependent upon TLR5 expressed on non-hemopioetic cells. Thus, loss of TLR5 increased the IL-1β/sIL-1Ra ratio on flagellin treatment, which correlated with increased inflammatory pathology in response to this product. Furthermore, the flagellin/TLR5 interaction was important for the induction of sIL-1Ra and limiting inflammatory pathology on Salmonella infection. Finally, reduced sIL-1Ra levels in TLR5KO mice correlated with spontaneous colitis. Taken together, we demonstrate that intestinal epithelia, despite not expressing IL-1β, secrete sIL-1Ra in a TLR5-dependent manner suggesting that loss of TLR5 may promote inflammation by increasing IL-1β activity. Thus, optimizing the balance between inflammasome cytokines and their endogenous inhibitors might prove a useful strategy to treat inflammatory disorders.
Carvalho
F A
FA
Department of Pathology, Emory University School of Medicine, Atlanta, Georgia, USA.
Aitken
J D
JD
Gewirtz
A T
AT
Vijay-Kumar
M
M
D000818:Animals; D020170:Caspase 1 / Q000378:metabolism; D002460:Cell Line; D003092:Colitis / Q000276:immunology; D004797:Enzyme-Linked Immunosorbent Assay; D005408:Flagellin / Q000276:immunology*; D015870:Gene Expression; D005786:Gene Expression Regulation; D058847:Inflammasomes; D007249:Inflammation / Q000276:immunology*; D053590:Interleukin 1 Receptor Antagonist Protein / Q000235:genetics / Q000378:metabolism*; D053583:Interleukin-1beta / Q000235:genetics* / Q000378:metabolism; D007413:Intestinal Mucosa / Q000276:immunology / Q000378:metabolism; D008264:Macrophages / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012480:Salmonella Infections / Q000276:immunology; D051198:Toll-Like Receptor 5 / Q000276:immunology* / Q000378:metabolism
D058847:Inflammasomes; D053590:Interleukin 1 Receptor Antagonist Protein; D053583:Interleukin-1beta; D016328:NF-kappa B; D012333:RNA, Messenger; D051198:Toll-Like Receptor 5; D005408:Flagellin; D020170:Caspase 1