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-Mediated Inflammatory Responses and Antiviral Defense in Liver Is TLR9-Independent but MyD88-Dependent during Murine Cytomegalovirus Infection1Department of Molecular Microbiology and Immunology, Division of Biology and Medicine, Brown University, Providence, RI 02912
Chemokine responses critical for inflammation and promotion of effective innate control of murine CMV (MCMV) in liver have been shown to be dependent on immunoregulatory functions elicited by IFN-
. However, it remains to be determined whether upstream factors that promote viral sensing resulting in the rapid secretion of IFN- in liver differ from those described in other tissues. Because plasmacytoid dendritic cells (pDCs) are known producers of high levels of systemic IFN- in response to MCMV, this study examines the in vivo contribution of pDCs to IFN- production in the liver, and whether production of the cytokine and ensuing inflammatory events are dependent on TLR9, MyD88, or both. We demonstrate that whereas MyD88 deficiency markedly impaired secretion of IFN-, production of the cytokine was largely independent of TLR9 signaling, in the liver. MyD88 and TLR9 were needed for IFN- production in the spleen. Moreover, hepatic but not splenic pDCs produced significant amounts of intracellular IFN- in the absence of TLR9 function during infection. Furthermore, production of CCL2, CCL3, and IFN-
, as well as the accumulation of macrophages and NK cells, was not affected in the absence of functional TLR9 in the liver. In contrast, these responses were dramatically reduced in MyD88–/– mice. Additionally, MyD88–/– but not TLR9–/– mice exhibited increased sensitivity to virus infection in liver. Collectively, our results define contrasting compartmental functions for TLR9 and MyD88, and suggest that the infected tissue site uniquely contributes to the process of virus sensing and regulation of localized antiviral responses.
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 National Institutes of Health Grant CA102708 (to T.S.-M.) and AI50644 (to W.-M.C.).
2 Current address: Science and Technology Department, Bryant University, 1150 Douglas Pike, Smithfield, RI 02917.
3 Address correspondence and reprint requests to Dr. Thais P. Salazar-Mather, Department of Molecular Microbiology and Immunology, Division of Biology and Medicine, Box G-B6, Biomedical Center, Room 575, Brown University, 171 Meeting Street, Providence, RI 02912. E-mail address: Thais_Mather{at}brown.edu
4 Abbreviations used in this paper: MCMV, murine CMV; DC, dendritic cell; pDC, plasmacytoid DC; PDCA-1, pDC Ag-1; ALT, alanine aminotransferase; WT, wild type; IRF, IFN regulatory factor.
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