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.
Highlights
Cardiovascular disease remains the leading cause of death globally with atherosclerosis as the major underlying cause [1, 2]
We found that macrophage lipid loading significantly suppressed the transcription of Ifnb1 (Figure 1C), as well as several members of its downstream IFN-stimulated genes (ISGs), including IFN-induced protein with tetratricopeptide repeats 1 (Ifit1), Ifit3, Isg15, MX dynamin like GTPase 1 (Mx1), C-X-C motif chemokine ligand 10 (Cxcl10), Ccl5 and Cxcl9 (Figure 1D; Supplementary Figure 1A)
To test whether IFN-β secretion was down regulated by foam cell formation, we stimulated macrophages with LPS and found IFN-β secretion to be significantly decreased after acLDLloading compared to controls (Figure 1F)
Summary
Cardiovascular disease remains the leading cause of death globally with atherosclerosis as the major underlying cause [1, 2]. Familial hypercholesterolemia (FH) patients have elevated levels of serum low density lipoprotein (LDL) that have been associated with premature atherosclerosis [1, 3,4,5]. Lifelong LDL cholesterol-lowering treatment effectively reduces cardiovascular events in FH patients. LDL is modified within the arterial wall triggering endothelial and immune cell activation and subsequent recruitment of immune cells like monocytes [8]. When monocytes enter the arterial intima, they differentiate into macrophages [9]. The various functions that macrophages can acquire are essential for atherosclerotic plaque development, stability and clinical outcome [9, 15, 16]
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
