High-density lipoprotein suppresses the type i interferon response, a family of potent antiviral immunoregulators, in macrophages challenged with lipopolysaccharide

Masashi Suzuki, David K. Pritchard, Lev Becker, Andrew N. Hoofnagle, Natsuko Tanimura, Theo K. Bammler, Richard P. Beyer, Roger Bumgarner, Tomas Vaisar, Maria C. De Beer, Frederick C. De Beer, Kensuke Miyake, John F. Oram, Jay W. Heinecke

Research output: Contribution to journalArticlepeer-review

97 Scopus citations

Abstract

Background-: High-density lipoprotein (HDL) protects the artery wall by removing cholesterol from lipid-laden macrophages. However, recent evidence suggests that HDL might also inhibit atherogenesis by combating inflammation. Methods and results-: To identify potential antiinflammatory mechanisms, we challenged macrophages with lipopolysaccharide, an inflammatory microbial ligand for Toll-like receptor 4. HDL inhibited the expression of 30% (277 of 911) of the genes normally induced by lipopolysaccharide, microarray analysis revealed. One of its major targets was the type I interferon response pathway, a family of potent viral immunoregulators controlled by Toll-like receptor 4 and the TRAM/TRIF signaling pathway. Unexpectedly, the ability of HDL to inhibit gene expression was independent of macrophage cholesterol stores. Immunofluorescent studies suggested that HDL promoted TRAM translocation to intracellular compartments, which impaired subsequent signaling by Toll-like receptor 4 and TRIF. To examine the potential in vivo relevance of the pathway, we used mice deficient in apolipoprotein A-I, the major protein of HDL. After infection with Salmonella typhimurium, a Gram-negative bacterium that expresses lipopolysaccharide, apolipoprotein A-I-deficient mice had 6-fold higher plasma levels of interferon-β, a key regulator of the type I interferon response, than did wild-type mice. Conclusions-: HDL inhibits a subset of lipopolysaccharide-stimulated macrophage genes that regulate the type I interferon response, and its action is independent of sterol metabolism. These findings raise the possibility that regulation of macrophage genes by HDL might link innate immunity and cardioprotection.

Original languageEnglish
Pages (from-to)1919-1927
Number of pages9
JournalCirculation
Volume122
Issue number19
DOIs
StatePublished - Nov 9 2010

Keywords

  • chemokines
  • cytokines
  • interferon regulatory factor 7
  • lipid cell membrane
  • myeloid differentiation factor 88

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine
  • Physiology (medical)

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