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

Abstract

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.

Commentary: Monocyte and macrophage lipid accumulation results in down-regulated type-I interferon responses

“…The study analyzed four public and newly generated transcriptomic datasets, including: (1) bone marrow-derived macrophages (BMDMs) with or without loading of acetylated low-density lipoprotein (ac-LDL); (2) peritoneal macrophages derived from wildtype and Apoe −/− mice; (3) human monocytes from familial hypercholesterolemia patients and healthy controls; 4) BMDMs with or without the treatment of LXR-agonist GW3965. The results support that ac-LDL loading in murine and human macrophages specifically suppressed interferon-β (IFN-β) secretion and the expression of IFN-stimulated genes (ISGs), but not many other pro-inflammatory genes ( 9 ). The downregulation of ISGs could be rescued by exogenous IFN-β supplementation.…”

“…In this issue of Frontiers in Cardiovascular Medicine , leveraging transcriptomic data analyses, Willemsen et al moved one important step forward toward addressing how foamy cells are less inflammatory ( 9 ). The study analyzed four public and newly generated transcriptomic datasets, including: (1) bone marrow-derived macrophages (BMDMs) with or without loading of acetylated low-density lipoprotein (ac-LDL); (2) peritoneal macrophages derived from wildtype and Apoe −/− mice; (3) human monocytes from familial hypercholesterolemia patients and healthy controls; 4) BMDMs with or without the treatment of LXR-agonist GW3965.…”

“…The downregulation of ISGs could be rescued by exogenous IFN-β supplementation. LXR activation suppressed the expression of ISGs, resembling the effects of lipid loading ( 9 ). Monocytes of familial hypercholesterolemia patients also show a deactivated IFN signature which was restored by lipid-lowering therapy ( 9 ).…”

“…LXR activation suppressed the expression of ISGs, resembling the effects of lipid loading ( 9 ). Monocytes of familial hypercholesterolemia patients also show a deactivated IFN signature which was restored by lipid-lowering therapy ( 9 ). The results further strengthened the notion that lipid-loaded foamy macrophages of mice and humans are less inflammatory and the specific involvement of perturbed type-I IFN responses ( 9 ).…”

“…Many questions remain unanswered. Beyond the role of LXR activation ( 9 ), if and how additional molecular mechanisms may be involved in suppressing the expression of ISGs in foamy macrophages remain undetermined. The current analyses highlighted a transcriptomic signature of suppressed IFN-β responses that is consistent in foamy macrophages in vitro and ex vivo , yet the differences among datasets may provide additional insights.…”