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* Section of Endocrinology, Department of Internal Medicine,
Section of Cardiovascular Medicine, Department of Internal Medicine, and
Howard Hughes Medical Institute and Department of Immunobiology, Yale School of Medicine, New Haven, CT 06520;
Department of Endocrinology, Qilu Hospital and
¶ Department of Cardiology, Shandong Provincial Hospital, Shandong University, Jinan, China;
|| Centre d’Immunologie de Marseille Luminy, INSERM Unité 631, Centre National de la Recherche Scientifique Unité Mixte de Recherche 6102, Université de la Méditerranée, Campus de Luminy, Case 906, Marseille, France;
# Department of Cellular and Molecular Medicine, University of Bristol, University Walk, Bristol, United Kingdom; and
** Center of Autoimmune Hepatitis, You-An Hospital, Capital University of Medicine, Beijing, China
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–/– mice were protected from Con A-induced hepatitis. Moreover, splenocytes from TLR3–/– mice proliferated 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–/– mice engrafted with WT hematopoietic cells were protected in a similar manner to WT mice reconstituted with TLR3–/– 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 costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
1 This work was supported by a pilot grant from the Yale Liver Center (P38, DK034989) and Animal Genetic Core of Yale Diabetes Endocrine Research Center (DK-02-003). X.X. is a scholarship recipient from the China Scholarship Council (2007-102113).
2 Address correspondence and reprint requests to Dr. Li Wen, Section of Endocrinology, Department of Internal Medicine, Yale School of Medicine, 330 Cedar Street, New Haven, CT 06520. E-mail address: li.wen{at}yale.edu
3 Abbreviations used in this paper: PAMP, pathogen-associated molecular pattern; ALT, alanine aminotransferase; MNC, mononuclear cell; WT, wild type; DAMP, damaged tissue-associated molecular pattern; BM, bone marrow; Treg, regulatory T cell; PDL-1, programmed cell death ligand 1.
4 The online version of this article contains supplemental material.
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