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

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

Published In Circulation, (2010 Nov 09)

Abstract: 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.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.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.

PubMed ID: 20974999

MeSH Terms: Animals; Chemokine CXCL10/secretion; Chemokines/genetics; Cytokines/genetics; Gene Expression Regulation/drug effects; Gene Expression Regulation/physiology; Immunosuppression; Interferon Type I/immunology*; Interferon-beta/secretion; Interleukin-12/secretion; Lipopolysaccharides/pharmacology*; Lipoproteins, HDL/pharmacology*; Macrophages/drug effects; Macrophages/immunology*; Mice; Mice, Inbred C57BL; RNA, Messenger/genetics; Signal Transduction/physiology; Thioglycolates/pharmacology; Toll-Like Receptor 4/agonists; Toll-Like Receptor 4/genetics; Toll-Like Receptors/genetics