Laboratory of Mucosal ImmunologyIn the Department of Medicine and Pediatrics
Director: Dr. Martin Kagnoff

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Press Release

by Dr. Martin Kagnoff

        The study, “TLR3, TRIF, and Caspase 8 Determine Double-Stranded RNA-Induced Epithelial Cell Death and Survival in Vivo,” shows that double-stranded RNA (dsRNA), which is characteristic of certain viral infections, activates a Toll-like receptor 3 (TLR3) signaling pathway in the intestinal epithelial cells (IECs) that line the small intestine and results in the death of those cells. IECs form the surface lining of small intestinal villi, which are finger-like projections that increase the surface area available for the absorption of nutrients from digested food. It is those IECs that are the targets of the dsRNA-induced cell death, which results in shortening of the villi and diarrhea. Disorders of the small intestine, such as celiac disease and certain intestinal virus infections (e.g. Rotavirus infection) are characterized by villus shortening in the small intestine and abnormalities in the absorption of nutrients. Epithelial cell death occurred by a process known as apoptosis, which is a type of programmed cell death. Importantly, despite these dramatic changes to the small intestine, the damage to the small intestinal structure was transient, since mice exposed to dsRNA survived and intestinal structure returned to normal within 48 hours.

        The researchers found that signaling induced by dsRNA occurred through TLR3 and the adaptor molecule TRIF and was preceded by increased activation of caspase 3 and 8 in the epithelial cells. Those caspases are enzymes that mediate apoptosis by cleaving cellular proteins. The scientists discovered that mice lacking TLR3 or its downstream adaptor TRIF were completely protected from dsRNA-induced IEC apoptosis. Further, they demonstrated that caspase 8 signaling in IECs was required for IEC apoptosis and recovery from villus shortening as mice lacking caspase 8 in IECs developed complete epithelial destruction in the small intestine and died. This finding suggests that intact caspase 8 signaling in the epithelium serves a protective function in response to dsRNA-activated signaling. They showed that IEC apoptosis was independent of other signaling mechanisms, leading the researchers to conclude that dsRNA activation of the TLR3-TRIF-caspase 8 signaling pathway in IECs has a significant impact on the structure and function of small intestinal mucosa. The authors suggest that signaling through this pathway may play a protective role during infection with viral pathogens, whereby increased IEC death and fluid loss may result in reduced viral load in the small intestine. Other contributors to the study include first author Christopher S. McAllister, and Omar Lakhdari, Guillaume Pineton de Chambrun, Mélanie G. Gareau, Alexis Broquet, Gin Hyug Lee, Steven Shenouda, and Lars Eckmann. The study was supported by National Institutes of Health Grants DK35108 and DK80506 and by a grant from the William K. Warren Foundation.

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