High-Density Lipoprotein Suppresses the Type I Interferon Response, a Family of Potent Antiviral Immunoregulators, in Macrophages Challenged With Lipopolysaccharide

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-␤, 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. Key Words: chemokines Ⅲ cytokines Ⅲ interferon regulatory factor 7 Ⅲ lipid cell membrane Ⅲ myeloid differentiation factor 88 H igh-density lipoprotein (HDL) protects against vascular disease by removing cholesterol from artery wall macrophages through reverse cholesterol transport. [1][2][3][4] There is mounting evidence, however, that it has additional antiatherosclerotic effects. 2,[5][6][7][8] One such activity may be modulation of the inflammatory response of the innate immune system. 9 -14 Editorial see p 1900 Clinical Perspective on p 1927Two cholesterol-transporting proteins, ABCA1 and ABCG1, might link HDL to both cholesterol removal and regulation of inflammation. 10 -12 Both membrane-associated ATP-binding cassette transporters are found in macrophages. ABCA1 promotes cholesterol efflux to lipid-poor apolipoprotein (apo) A-I, the major HDL protein, and ABCG1 induces cholesterol efflux to intact HDL particles. 10 Macrophages isolated from mice with genetically engineered deficiencies in ABCA1 and/or ABCG1 overexpress well-known inflammatory genes such as tumor necrosis factor-␣ (TNF-␣), interleukin (IL) -1␤, and IL-8 when the cells are stimulated with bacterial lipopolysaccharide (LPS). 11 In both macrophages and endothelial cells, the antiinflammatory effects of HDL have been proposed to reflect changes in membrane chole...

HDL in Infectious Diseases and Sepsis

“…rHDL significantly reduced endotoxemia-induced inflammatory response, as it reduced clinical symptoms, reduced inflammatory cytokine (TNF-α, IL-6, IL-8) production, and attenuated LPS-induced leukocyte activation, in part due to the downregulation of the main LPS receptor monocyte-bound CD14 (Pajkrt et al 1996). In LPS-challenged macrophages, HDLs selectively inhibit the activation of type I IFN response genes (Suzuki et al 2010), which play a critical role in the antiviral response of cells, although emerging evidence also implicates this response in host defense during bacterial infection. This inhibitory effect of HDL does not require LPS binding to lipoproteins (Suzuki et al 2010).…”

“…In LPS-challenged macrophages, HDLs selectively inhibit the activation of type I IFN response genes (Suzuki et al 2010), which play a critical role in the antiviral response of cells, although emerging evidence also implicates this response in host defense during bacterial infection. This inhibitory effect of HDL does not require LPS binding to lipoproteins (Suzuki et al 2010). HDLs (and apoA-I) attenuate also LPS-induced neutrophil activation (Murphy et al 2011).…”

Naturally occurring variant of mouse apolipoprotein A-I alters the lipid and HDL association properties of the protein

“…During the acute phase response, levels of serum amyloid A increase dramatically and are found in the plasma associated with HDL-sized lipoproteins, whereas ApoA-I may dissociate from HDL and be catabolized, reducing plasma levels of ApoA-I HDL ( 46 ). Suzuki et al (47) have recently shown that HDL is protective in mice infected with Salmonella typhimurium , preventing increases in plasma levels of interferon-␤ . The greater HDL affi nity of one ApoA-I protein over another may play a role in the response to an infl ammatory challenge.…”

Inverse association of plasma level of high-density lipoprotein cholesterol with intracerebral hemorrhage

“…In recent cell culture studies with animal and human cells, HDL promoted cholesterol effl ux from macrophage foam cells in atheromatous vessels, reducing the cholesterol burden and macrophage-driven infl ammation ( 33,35 ). HDL also inhibits the type I interferon response pathway independently of macrophage cholesterol stores ( 36 ) and activates the complement cascade ( 37,38 ). Furthermore, HDL-C not only inhibits LDL-induced lipid hydroperoxide Supplemental Material can be found at:…”