HepatitisInflammatory Regulation by TLR3 in Acute

TLR3 is known to respond to dsRNA from viruses, apoptotic cells, and/or necrotic cells. Dying cells are a rich source of ligands that can activate TLRs, such as TLR3. TLR3 expressed in the liver is likely to be a mediator of innate activation and inflammation in the liver. The importance of this function of TLR3 during acute hepatitis has not previously been fully explored. We used the mouse model of Con A-induced hepatitis and observed a novel role for TLR3 in hepatocyte damage in the absence of an exogenous viral stimulus. Interestingly, TLR3 expression in liver mononuclear cells and sinus endothelial cells was up-regulated after Con A injection and TLR3 (cid:1) / (cid:1) mice were protected from Con A-induced hepatitis. Moreover, splenocytes from TLR3 (cid:1) / (cid:1) mice pro-liferated less to Con A stimulation in the presence of RNA derived from damaged liver tissue compared with wild-type (WT) mice. To determine the relative contribution of TLR3 expression by hematopoietic cells or nonhematopoietic to liver damage during Con A-induced hepatitis, we generated bone marrow chimeric mice. TLR3 (cid:1) / (cid:1) mice engrafted with WT hematopoietic cells were protected in a similar manner to WT mice reconstituted with TLR3 (cid:1) / (cid:1) bone marrow, indicating that TLR3 signaling in both nonhematopoietic and hematopoietic cells plays an important role in mediating liver damage. In summary, our data suggest that TLR3 signaling is necessary for Con A-induced liver damage in vivo and that TLR3 regulates inflammation and the adaptive T cell immune response in the absence of viral infection. The Journal of Immunology, 2009, diabetic (NOD) mice spontaneous autoimmune diabetes, the genetic makeup of NOD mice to other autoimmune syndromes, thyroiditis, peripheral polyneuropathy, a systemic lupus erythematosus-like disease, and possibly other autoimmune disorders 17). In this study, we used wild-type (WT) and TLR3 (cid:2) / (cid:2) mice on both NOD and C57BL/6 genetic back-grounds, and tested the hypothesis that endogenous ligands released in the course of Con A-induced hepatocyte damage can activate innate immunity via TLR3 signaling. Our results showed that in the absence of an exogenous viral pathogen, TLR3 activation was important for the initiation and the amplification of hepatic inflammation possibly via recognition of cellular by-products from apoptotic and necrotic cells. Our results also support a novel notion that TLR3 is an endogenous inflammatory regulator in acute inflammation, such as Con A-induced autoimmune hepatitis. Student’s t test wherever appropriate. A p (cid:6) 0.05 was considered statisti- cally significant. These results suggest that functional TLR3 in both hematopoietic and nonhematopoietic cells is important in liver damage in this model system. Moreover, these results indicate a novel role of TLR3 in the acute inflammation, which is not associated with viral infection or mediated by type 1 IFN. Our results suggest that TLR3 is not only a receptor for PAMPs, such as viral dsRNA, but likely to be a receptor for DAMPs, which induce inflammation in the Con A-induced hepatitis experimental system.

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