IRF7 Expression Drives Instability in Atherosclerotic Plaques
Atherosclerosis is the largest cause of human mortality, a growth of fatty plaques in blood vessel walls that narrow and weaken vessels. The structure and composition of plaques can vary considerably between people and within one individual. The most dangerous plaques are those with more fat and less structural material, as these are prone to rupture, leading to a downstream blockage and a heart attack or stroke. A plaque is a toxic environment that draws in macrophage cells that attempt to repair the lesion, but instead are overwhelmed, killed, and add their mass to the plaque. Initially, circulating monocyte cells arrive at a plaque and turn into macrophages, but in later stages an almost cancerous process causes smooth muscle cells in the vascular wall to turn into macrophages to further accelerate plaque growth and instability. Here, researchers find a way to potentially interfere in this process, and thus greatly reduce the formation of unstable plaques that are prone to rupture.
Smooth muscle cells (SMCs) exhibit remarkable plasticity, undergoing extensive phenotypic switching to generate a highly heterogeneous population within atherosclerotic plaques. While recent studies have highlighted the contribution of SMC-derived macrophage-like cells to plaque inflammation, the specific molecular drivers governing the transition to these pathogenic states remain poorly understood.
Here, we re-analyzed single-cell RNA sequencing data from lineage-traced mice to dissect SMC heterogeneity during atherogenesis. Trajectory analysis revealed that SMCs transdifferentiate into a distinct pro-inflammatory macrophage-like subpopulation via an intermediate "stem-endothelial-monocyte" cell state. Integrated gene regulatory network inference and in silico perturbation modeling identified interferon regulatory factor 7 (IRF7) as a master transcriptional regulator orchestrating this specific pathogenic transition.
Clinically, IRF7 expression was significantly upregulated in unstable and advanced human atherosclerotic plaques, correlating strongly with inflammatory macrophage burden. In vivo, ApoE knockout mice challenged with a high-fat diet exhibited robust upregulation of IRF7 in aortic plaques, which co-localized with macrophage markers. Crucially, SMC-specific knockdown of Irf7 significantly attenuated atherosclerotic plaque progression, reduced necrotic core formation, and enhanced fibrous cap stability. Mechanistically, Irf7 silencing preserved the contractile SMC phenotype and inhibited the accumulation of pro-inflammatory SMC-derived macrophage-like cells within the lesion.