Chen HJ. J Exp Med. 2020 Jan 6;217(1). pii: e20190459.
Atherosclerosis, a chronic inflammatory disorder, is the main fundamental causal factor of CVDs with the lipid aggregation in the arterial intima where modified low-density lipoprotein (mLDL) deposition stimulates the recruitment of blood-derived immune cells and activates inflammatory cascades. Interferon (IFNs) are a group of cytokines entitled by their distinctives of viral intervention. IFNs can be categorised into three families (type-I, -II, and -III) as per the protein structure and the receptors they signal through. Type-I IFNs are main immune modulator modifying both innate and adaptive immunity. From both human and murine studies, evidences were assembled which supports their role in atherogenesis and associated clinical evidences. Experimental data show that systemic or intraplaque type-I IFNs activates endothelium and immune cells, promotes foam cell formation, modifies progenitor cell function, and improves pro-inflammatory leukocyte enrollment to arteries causing degeneration of atherogenesis.
Thus, Chen HJ conducted a study to review the role of type-I IFNs in atherogenesis and explore the potential opportunities to reduce inflammation for prevention and therapeutic interference of atherosclerosis. In specific, the impact of type-I IFNs on various atherogenic cell types were described, their involvement in accelerated atherosclerosis were highlighted in patients with IFN-correlated autoimmune disorders, and a multi-target therapy of anti-type-I IFN in disease was discussed.
IFNs have been familiar for their antiviral activity for decades. The type-I IFN receptor (IFNAR) is a heterodimer of IFNAR1 and IFNAR2; the type-II IFN receptor (IFNGR) comprises of subunits IFNGR1 and IFNGR2; and the type-III IFN receptor (IFNLR) included IFNLR1 and IL-10 receptor β. In humans, type-I IFNs embrace of 13 IFN-α isoforms (14 in mice), IFN-β, IFN-ε, IFN-κ, IFN-δ, and IFN-ω, which all indicate via IFNAR. IFN-α and IFN-β are the most distinguished and the most predominantly articulated type-I IFNs. In atherosclerosis development, plaque-residing monocytes and macrophages are extremely heterogeneous populations with different functions. These cells mainly take up the accumulated lipids in the arterial intima. Type-I IFN treatment enabled lipid uptake in both human and mouse monocytes/ macrophages through up-regulation of scavenger receptors class A and showed enhanced foam cell formation. Both pro- and anti-inflammatory phenotypes can be exerted by Type-I IFN–activated macrophages. Both mouse and human macrophages’ inflammatory cytokine production and inflammasome activity is restrained by Type-I IFNs with anti-inflammatory cytokine induction, such as IL-10, epigenetic regulation impacting chromatin availability, and metabolic rewiring. An isolated myeloid dendritic cells (mDCs) and macrophages from IFN-α–treated human plaque tissue ex vivo exhibited remarkably enhanced LPS-triggered TNF secretion as well as other proatherogenic cytokines such as IL-12, IL-23, and MMP-9 production and CCL5 impelled neutrophil enrollment to the arterial wall in mice, which is persuaded in type-I IFN–stimulated macrophages and ECs. In humans and mice, the presence of NET structures are seen in atherosclerotic plaques and arterial thrombi, particularly in cholesterol-rich or erosion-prone areas. Additionally, LDGs are effective in generating an IFN signature in ECs, thus distorting their differentiation from the progenitors. While in murine models, type-I IFN administration aggravates atherosclerosis, both direct and indirect impacts of type-I IFNs could show outcome in clinical evidence to the plaque-residing cells in humans, particularly in individuals with enhanced IFN signatures (Figure 1). Type-I IFNs play definite roles in various autoimmune disorders. The mononuclear cells from untreated multiple sclerosis (MS) patients generally show decreased response to type-I IFNs and the signature gene expression as compared to heathy controls.
Thus, it was concluded that advanced understanding of the genetic and epigenetic management and the biological base of IFN signaling might facilitate to mediate in cardiovascular and autoimmune disorders through fine-tuned modulation of type-I IFN indicating with targeted pharmacological technologies, which might serve as a auspicious and safe therapy strategy for atherosclerosis in patients with autoimmune disorders.
Figure 1: Type-I IFNs affect atherosclerosis
ECs: Endothelial cells; LDGs: Low-density granulocytes
