Recognition of Double-Stranded RNA by TLR3 Induces Severe Small Intestinal Injury in Mice

Abstract

The role of TLRs on intestinal epithelial cells (IECs) is controversial, and the mechanisms by which TLRs influence mucosal homeostasis are obscure. In this study, we report that genomic dsRNA from rotavirus, and its synthetic analog polyinosinic-polycytidylic acid (poly(I:C)), induce severe mucosal injury in the small intestine. Upon engaging TLR3 on IECs, dsRNA triggers IECs to secrete IL-15, which functions to increase the percentage of CD3+NK1.1+ intestinal intraepithelial lymphocytes (IELs) and enhances the cytotoxicity of IELs. Moreover, The CD3+NK1.1+ IELs are proved as CD8αα+ IELs. These results provide direct evidence that abnormal TLR3 signaling contributes to breaking down mucosal homeostasis and the first evidence of pathogenic effects mediated by CD8αα+ IELs. The data also suggest that genomic dsRNA may be involved in the pathogenesis of acute rotavirus gastroenteritis.

Sensing and Control of Bluetongue Virus Infection in Epithelial Cells via RIG-I and MDA5 Helicases

“…Recently, the MAVS/RLR pathway was found to play an important role in IFN-␤ production in rotavirus-infected cells, suggesting that some conserved mechanism exists among the members of the Reoviridae family (5, 57). Rotavirus genomic dsRNA was shown to trigger the IFN response (7,68). It would be interesting to determine whether this mechanism is conserved for BTV.…”

The toll-like receptor 3 pathway in homeostasis, responses to injury and wound repair

“…Levels of inducible nitric oxide synthase, cyclooxygenase-2, serum CXCL1/KC (derived from keratinocytes) and amyloid A were also reduced in poly(IC)-treated mice [69]. However, other studies actually implicate TLR3 signalling in inducing acute injury in gut epithelia [70][71][72]. Intraperitoneal injection of rotavirus dsRNA resulted in severe injury in the small intestine as characterized by thinning of the intestinal wall, erosion of villi and the mucus membrane, and weight loss; Tlr3 -/-mice were protected from such effects [70][71][72].…”

“…However, other studies actually implicate TLR3 signalling in inducing acute injury in gut epithelia [70][71][72]. Intraperitoneal injection of rotavirus dsRNA resulted in severe injury in the small intestine as characterized by thinning of the intestinal wall, erosion of villi and the mucus membrane, and weight loss; Tlr3 -/-mice were protected from such effects [70][71][72]. Poly(IC) administration also upregulated serum levels of several cytokines including IL-15 and IFN- [70].…”

“…Intraperitoneal injection of rotavirus dsRNA resulted in severe injury in the small intestine as characterized by thinning of the intestinal wall, erosion of villi and the mucus membrane, and weight loss; Tlr3 -/-mice were protected from such effects [70][71][72]. Poly(IC) administration also upregulated serum levels of several cytokines including IL-15 and IFN- [70]. IL-15 was shown to have a non-redundant role in driving TLR3-mediated injury, whereas IFN- had a protective effect [70].…”

“…Poly(IC) administration also upregulated serum levels of several cytokines including IL-15 and IFN- [70]. IL-15 was shown to have a non-redundant role in driving TLR3-mediated injury, whereas IFN- had a protective effect [70]. Interestingly, this IL-15-dependent mechanism of intestinal damage has previously been reported in human patients with celiac disease, where the activation of intraepithelial cytotoxic T lymphocytes by IL-15 led to uncontrolled cell destruction and atrophy [73][74][75][76].…”