Intestinal inflammation in mice deficient in Tir8 , an inhibitory member of the IL-1 receptor family

Abstract

TIR8, also known as single Ig IL-1-related receptor, is a member of the IL-1 receptor͞Toll-like receptor (TLR) superfamily, which acts as an intracellular decoy for components of the signaling pathway. Here we report that Tir8 has a unique pattern of expression, which includes mucosal tissues and dendritic cells (DC). Tir8-deficient DC showed increased cytokine production in response to TLR agonists (lipopolysaccharide, CpG oligodeoxynucleotides). Tir8-deficient mice had normal susceptibility to systemic lipopolysaccharide toxicity and to i.p. or s.c. inflammation. However, Tir8-deficient mice were more susceptible to intestinal inflammation. Thus, TIR8 represents a negative pathway of regulation of the IL-1 receptor͞TLR system, expressed in epithelial cells and DC, crucial for tuning inflammation in the gastrointestinal tract.

The non-muscle-myosin-II heavy chain Myh9 mediates colitis-induced epithelium injury by restricting Lgr5+ stem cells

“…7d). DSS-induced acute colitis is a widely employed model to study colitis, which is thought to be provoked by inflammation 13,38,39 . However, recent studies suggest that damage of colonic stem cells could be a major cause [13][14][15] .…”

TIR, CARD and PYRIN: three domains for an antimicrobial triad

“…Interestingly, SIGIRR is highly expressed in the intestinal mucosa and SIGIRR-deficient mice have higher susceptibility to dextran-sulfate sodium-induced colitis stressing the idea that this negative regulator plays a key role in downregulating signals derived from the commensal flora in the intestinal tract. 34 A number of intracellular negative regulators also exist. Molecules like MyD88short, SOCS1 and IRAKM all act by interfering with specific points in the pathway downstream of TLRs and blocking activation of the NF-kB pathway.…”

TLR Signaling in the Gut in Health and Disease

“…Animals that are deficient in TIR8/SIGIRR are more susceptible to colitis induced by dextran sodium sulfate (DSS) (24,25). Although not formally a TLR inhibitor, peroxisome proliferator-activated receptor-␥, inhibits NF-B activation and reduces inflammation in animal models of colitis.…”

“…The TLR inhibitory molecule TIR8/SIGIRR is expressed by both intestinal epithelial cells and dendritic cells. The increased sensitivity of TIR8-deficient mice to DSS-induced colitis may therefore be due to a defect in dendritic cell function to limit Th1-dependent damage (24).…”