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A role for IRF3-dependent RXR repression in hepatotoxicity associated with viral infections

¹ Molecular Biology Institute, ² Howard Hughes Medical Institute, ³ Department of Pathology and Laboratory Medicine, ⁴ Department of Microbiology, Immunology, and Molecular Genetics, ⁵ Division of Dermatology, ⁶ Jonsson Comprehensive Cancer Center, and ⁷ Medical Scientist Training Program, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095

CORRESPONDENCE Genhong Cheng: genhongc{at}microbio.ucla.edu

Viral infections and antiviral responses have been linked to several metabolic diseases, including Reye's syndrome, which is aspirin-induced hepatotoxicity in the context of a viral infection. We identify an interferon regulatory factor 3 (IRF3)–dependent but type I interferon–independent pathway that strongly inhibits the expression of retinoid X receptor (RXR) and suppresses the induction of its downstream target genes, including those involved in hepatic detoxification. Activation of IRF3 by viral infection in vivo greatly enhances bile acid– and aspirin-induced hepatotoxicity. Our results provide a critical link between the innate immune response and host metabolism, identifying IRF3-mediated down-regulation of RXR as a molecular mechanism for pathogen-associated metabolic diseases.

Abbreviations used: 1,25(OH)₂D₃, 1,25-dihydroxyvitamin D3; 9cRA, 9-cis retinoic acid; ALT, alanine aminotransferase; ASA, acetylsalicylic acid; BMM, bone marrow–derived macrophage; FXR, farnesoid X receptor; H&E, hematoxylin and eosin; HDAC1, histone deacetylase 1; IRF, IFN regulatory factor; LCA, lithocholic acid; LXR, liver X receptor; PCN, pregnenolone-16-carbonitrile; polyI:C, polyinosine-polycytidylic acid; PPAR, peroxisome proliferator–activated receptor; PXR, pregnane X receptor; Q-PCR, quantitative PCR; RXR, retinoid X receptor; TLR, Toll-like receptor; TSA, trichostatin A; UGT1A6, uridine diphosphate glucuronosyltransferase 1A6; USF, upstream stimulatory factor; VDR, vitamin D receptor; VSV, vesicular stomatitis virus.

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