Type-I interferons in atherosclerosis

Abstract

The contribution of dyslipidemia and inflammation in atherosclerosis is well established. Along with effective lipid-lowering treatments, the recent success of clinical trials with anti-inflammatory therapies and the accelerated atherosclerosis in many autoimmune diseases suggest that targeting inflammation may open new avenues for the prevention and the treatment for cardiovascular diseases (CVDs). In the past decades, studies have widened the role of type-I interferons (IFNs) in disease, from antivirus defense to autoimmune responses and immuno-metabolic syndromes. While elevated type-I IFN level in serum is associated with CVD incidence in patients with interferonopathies, experimental data have attested that type-I IFNs affect plaque-residing macrophages, potentiate foam cell and extracellular trap formation, induce endothelial dysfunction, alter the phenotypes of dendritic cells and T and B lymphocytes, and lead to exacerbated atherosclerosis outcomes. In this review, we discuss the production and the effects of type-I IFNs in different atherosclerosis-associated cell types from molecular biology studies, animal models, and clinical observations, and the potential of new therapies against type-I IFN signaling for atherosclerosis.

Figure 1.

Simplified schematic of type-I IFN induction and major IFNAR signaling pathways. Type-I IFNs are induced by nucleic acid or LPS activation of a variety of PRRs, including cytosolic nucleic acid sensors and TLRs. Activation of PRRs results in nuclear translocation of IRFs, which bind to the promoter region of type-I IFNs. IRF3-mediated IFN expression could be induced by STING (via cGAS), RIG-1, MDA5, TLR3, and TLR4 (through TRIF) while ligand engagement of TLR7/8 and TLR9 activate IRF7 and/or IRF5 via MyD88. Cytokines such as TNF can also induce type-I IFN expression through the TNFR-IRF1 signaling pathway. Secreted type-I IFNs bind autocinely/paracrinely to the IFNAR complex composed of IFNAR1 and IFNAR2, which consequently triggers cross-phosphorylation of TYK2 and JAK1 and activates different STAT homo/heterodimers controlling distinct transcription programs. ISGF3 consists of STAT1, STAT2, and IRF9 and binds to IFN-stimulated response element (ISRE) sequences upstream of ISGs and IRF7, while STAT1 homodimer induces IRF1 and pro-inflammatory gene expression via GASs binding. dsRNA, double-stranded RNA; ssRNA, single-stranded RNA.

Figure 2.

Type-I IFNs affect atherosclerosis. Type-I IFNs can be produced by monocytes, macrophages, pDCs, eosinophils, and B cells and LDGs in autoimmune patients. Locally and systemically elevated type-I IFNs result in increased foam cell formation, EC dysfunction, suppressed EPC maturation, enhanced NETosis, increased monocyte and neutrophil recruitment, and elevated immune cell activation. IFN-stimulated T cells exert stronger cytotoxic function to SMC via TRAIL. Myeloid APCs including macrophages and mDCs secrete higher levels of TNF, leading to IFN-β expression in ECs. Type-I IFN priming of IFN-producing cells such as pDCs, monocytes, B cells, ECs, and LDGs results in an autocrine feedback loop that exacerbates the pro-inflammatory microenvironment.

Figure 3.

The effect of type-I IFNs during atherosclerosis development in different models. Atherosclerosis is driven by predisposing risk factors such as dysregulated lipids, pro-inflammatory stimuli, and cytokines. The development of the lesion is characterized by lipid trapping, leukocyte infiltration and activation, foam cell formation, fibrous cap, and extracellular lipid core formation. In unstable, complex plaques, fibrous cap thinning and necrosis take place, which lead to plaque rupture. The dots, from left to right, represent the effect on the corresponding event due to “type-I IFNs, IFNAR signaling blockade in mice,” “lupus-prone mice or type-I IFN treatment in mice,” “anti-type-I IFN/IFNAR treatment in human,” and “interferonopathy patients or type-I IFN treatment in human,” respectively. For each dot, the left hemisphere of the dot indicates in vitro or ex vivo data, while the right means in vivo studies.