IRF7 orchestrates maladaptive smooth muscle cell phenotype switching in atherosclerosis

TL;DR

This study identifies IRF7 as a key driver of harmful smooth muscle cell changes in atherosclerosis, which could lead to new treatments for unstable artery plaques.

Contribution

The study identifies IRF7 as a master regulator of pathogenic smooth muscle cell transdifferentiation in atherosclerosis.

Findings

IRF7 orchestrates the transition of smooth muscle cells into pro-inflammatory macrophage-like cells in atherosclerotic plaques.

SMC-specific knockdown of Irf7 reduces plaque progression and stabilizes fibrous caps in mice.

High IRF7 expression correlates with plaque instability in human atherosclerosis.

Abstract

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 (macrophage 4) 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−/− 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 using an AAV-SM22α-shIRF7 vector 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.

These findings identify IRF7 as a critical checkpoint in maladaptive SMC phenotype switching. We demonstrate that IRF7 drives the transdifferentiation of SMCs into a pro-inflammatory macrophage-like state, thereby fueling plaque instability. Consequently, therapeutic strategies capable of inhibiting IRF7-mediated SMC plasticity may prove effective in stabilizing vulnerable atherosclerotic plaques.

Graphical AbstractSingle-cell RNA sequencing identifies the trajectory of SMC transdifferentiation into a pro-inflammatory macrophage-like state with IRF7 as the master regulator of this pathogenic transition. In human plaques, high IRF7 expression correlates with plaque instability. In vivo SMC-specific knockdown of Irf7 inhibits the maladaptive phenotypic switching and stabilizes the atherosclerotic plaque.

Single-cell RNA sequencing identifies the trajectory of SMC transdifferentiation into a pro-inflammatory macrophage-like state with IRF7 as the master regulator of this pathogenic transition. In human plaques, high IRF7 expression correlates with plaque instability. In vivo SMC-specific knockdown of Irf7 inhibits the maladaptive phenotypic switching and stabilizes the atherosclerotic plaque.

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