Projecting villi in the small intestine vastly increase the surface area of the gut, increasing its ability to absorb nutrients. Some food particles are visible in one of the crevices between villi. Scanning electron micrograph courtesy of Alan Boyde, Wellcome Images.
Signaling intestinal distress
Researchers at the University of California, San Diego School of Medicine have identified the signaling pathway involved in viral infections that provokes the intestinal epithelial cell death seen in some of those infections and other intestinal disorders like celiac disease.
The results of the study led by Martin F. Kagnoff, MD, professor of medicine and pediatrics and director of the Laboratory of Mucosal Immunology at UC San Diego, and colleagues, 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 that line the small intestine and results in the death of those cells. Their study has been published in the January 1 edition of The Journal of Immunology.
Disorders of the small intestine, including celiac disease and certain intestinal virus infections such as Rotavirus infection, are characterized by villus shortening in the small intestine and abnormalities in the absorption of nutrients. Intestinal epithelia 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 – a result of apoptosis, or programmed cell death – resulting in shortening of the villi and diarrhea. Importantly, despite dramatic changes to the small intestine, the researchers found that such damage to the small intestinal structure was transient, since mice exposed to dsRNA survived and intestinal structure returned to normal within 48 hours.
The scientists discovered that signaling induced by dsRNA occurred through TLR3 and the adaptor molecule TRIF, and was followed by increased activation of caspase 3 and 8 in the epithelial cells – enzymes that mediate apoptosis by cleaving cellular proteins.
Mice lacking TLR3 or its downstream adaptor TRIF were completely protected from dsRNA-induced IEC apoptosis. The study 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.
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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