Retinoid X receptor α attenuates host antiviral response by suppressing type I interferon

Nat Commun. 2014 Nov 24:5:5494. doi: 10.1038/ncomms6494.

Abstract

The retinoid X receptor α (RXRα), a key nuclear receptor in metabolic processes, is downregulated during host antiviral response. However, the roles of RXRα in host antiviral response are unknown. Here we show that RXRα overexpression or ligand activation increases host susceptibility to viral infections in vitro and in vivo, while Rxra-/- or antagonist treatment reduces infection by the same viruses. Consistent with these functional studies, ligand activation of RXR inhibits the expression of antiviral genes including type I interferon (IFN) and Rxra-/- macrophages produce more IFNβ than WT macrophages in response to polyI:C stimulation. Further results indicate that ligand activation of RXR suppresses the nuclear translocation of β-catenin, a co-activator of IFNβ enhanceosome. Thus, our studies have uncovered a novel RXR-dependent innate immune regulatory pathway, suggesting that the downregulation of RXR expression or RXR antagonist treatment benefits host antiviral response, whereas RXR agonist treatment may increase the risk of viral infections.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Active Transport, Cell Nucleus
  • Animals
  • Cell Line
  • Down-Regulation
  • Fatty Acids, Unsaturated / pharmacology
  • HEK293 Cells
  • Herpes Simplex / immunology
  • Herpesvirus 1, Human / immunology*
  • Humans
  • Interferon-beta / antagonists & inhibitors*
  • Interferon-beta / immunology
  • Ligands
  • Macrophages / immunology
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Poly I-C / pharmacology
  • RNA Interference
  • RNA, Small Interfering
  • Retinoid X Receptor alpha / antagonists & inhibitors
  • Retinoid X Receptor alpha / biosynthesis
  • Retinoid X Receptor alpha / genetics*
  • Tetrahydronaphthalenes / pharmacology
  • Vesicular Stomatitis / immunology
  • Vesicular stomatitis Indiana virus / immunology*
  • Viral Plaque Assay
  • beta Catenin / metabolism

Substances

  • AGN 194204
  • Fatty Acids, Unsaturated
  • Ligands
  • RNA, Small Interfering
  • Retinoid X Receptor alpha
  • Tetrahydronaphthalenes
  • beta Catenin
  • Interferon-beta
  • Poly I-C

Associated data

  • GEO/GSE62107