IRF7 orchestrates maladaptive smooth muscle cell phenotype switching in atherosclerosis

Abstract

Background 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.

Methods 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.

Results 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 knock-down of Irf7 using an AAV-SM22 α -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.

Conclusions 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.

Keywords

atherosclerosis / vascular smooth muscle cell / IRF7 / phenotype switching / single-cell RNA sequencing / transdifferentiation / inflammation / macrophage-like cells

Acknowledgements

This study was supported by the National Natural Science Foundation of China (grant No. 32171387). We would like to thank all members of our labs for fruitful scientific discussion and mutual support. We also extend our gratitude to the research team at Columbia University (Pan et al., 2020) for providing public access to the high-quality scRNA-seq dataset utilized in this study.

Author contributions

Rundong Cai (Conceptualization, Data curation, Formal analysis, Investigation, Methodology, Validation, Visualization, Writing—original draft, Writing—review & editing), Xin Chen (Data curation, Formal analysis, Investigation, Validation, Visualization, Writing—review & editing), Hongxia Zhang (Investigation), Xinghua Pan (Conceptualization, Methodology, Project administration, Supervision, Writing—review & editing), Chun Liang (Conceptualization, Methodology, Project administration, Supervision, Writing—review & editing), Haiying Zhu (Conceptualization, Methodology, Writing—original draft, Writing—review & editing), Wanrong Xie (Visualization), Qi Wang (Visualization).

Supplementary material

Supplementary material is available at PCMEDI online.

Conflicts of interest

None declared. In addition, as an Associate Editor of Precision Clinical Medicine, the corresponding author X.P. was blinded from reviewing and making decisions on this manuscript.

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