Monocyte and Macrophage Lipid Accumulation Results in Down-Regulated Type-I Interferon Responses

Frontiers in Cardiovascular Medicine

article

Lisa Willemsen¹  Hung-Jen Chen¹  Cindy P. A. A. van Roomen¹  Guillermo R. Griffith¹  Ricky Siebeler¹  Annette E. Neele¹  Jeffrey Kroon²  Marten A. Hoeksema¹  Menno P. J. de Winther¹ 

[1]Department of Medical Biochemistry, Experimental Vascular Biology, Amsterdam Cardiovascular Sciences, Amsterdam Infection and Immunity, University of Amsterdam

[2]Department of Experimental Vascular Medicine, Amsterdam Cardiovascular Sciences, University of Amsterdam

关键词: atherosclerosis;    macrophage;    monocyte;    foam cell formation;    cholesterol;    inflammation;    interferon response;    immunometabolism;   

DOI  :  10.3389/fcvm.2022.829877

学科分类：地球科学(综合)

来源: Frontiers

【 摘 要 】

Macrophages are critical components of atherosclerotic lesions and their pro- and anti-inflammatory responses influence atherogenesis. Type-I interferons (IFNs) are cytokines that play an essential role in antiviral responses and inflammatory activation and have been shown to promote atherosclerosis. Although the impact of type-I IFNs on macrophage foam cell formation is well-documented, the effect of lipid accumulation in monocytes and macrophages on type-I IFN responses remains unknown. Here we examined IFN stimulated (ISG) and non-ISG inflammatory gene expression in mouse and human macrophages that were loaded with acetylated LDL (acLDL), as a model for foam cell formation. We found that acLDL loading in mouse and human macrophages specifically suppressed expression of ISGs and IFN-β secretion, but not other pro-inflammatory genes. The down regulation of ISGs could be rescued by exogenous IFN-β supplementation. Activation of the cholesterol-sensing nuclear liver X receptor (LXR) recapitulated the cholesterol-initiated type-I IFN suppression. Additional analyses of murine in vitro and in vivo generated foam cells confirmed the suppressed IFN signaling pathways and suggest that this phenotype is mediated via down regulation of interferon regulatory factor binding at gene promoters. Finally, RNA-seq analysis of monocytes of familial hypercholesterolemia (FH) patients also showed type-I IFN suppression which was restored by lipid-lowering therapy and not present in monocytes of healthy donors. Taken together, we define type-I IFN suppression as an athero-protective characteristic of foamy macrophages. These data provide new insights into the mechanisms that control inflammatory responses in hyperlipidaemic settings and can support future therapeutic approaches focusing on reprogramming of macrophages to reduce atherosclerotic plaque progression and improve stability.

【 授权许可】

CC BY