TLR5 Activation Induces Secretory Interleukin-1 Receptor Antagonist (sIL-1Ra) and Reduces Inflammasome-associated Tissue Damage

TLR5-mediated detection of flagellin induces NF-κB mediated transcription of host defense gene expression whereas recognition of intracellular flagellin by IPAF results in maturation/secretion of the inflammasome cytokine IL-1β. The potent effects of IL-1β are counter-regulated by secretory interleukin-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 while 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 upon flagellin treatment, which correlated with increased inflammatory pathology in response to this product. Furthermore, the flagellin/TLR5 interaction was important for induction of sIL-1Ra and limiting inflammatory pathology upon Salmonella infection. Lastly, 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 loss of TLR5 may promote inflammation via increasing IL-1β activity. Thus, optimizing the balance between inflammasome cytokines and their endogenous inhibitors might prove a useful strategy to treat inflammatory disorders.