Aberrant mitochondrial DNA synthesis in macrophages exacerbates inflammation and atherosclerosis
Niranjana Natarajan, Jonathan Florentin, Ebin Johny, Hanxi Xiao, Scott O'Neil, Liqun Lei, Jixing Shen, Lee Ohayon, Aaron R. Johnson, Krithika Rao, Xiaoyun Li, Yanwu Zhao, Yingze Zhang, Sina Tavakoli, Sruti Shiva, Jishnu Das, Partha Dutta
Abstract
There is a large body of evidence that cellular metabolism governs inflammation, and that inflammation contributes to the progression of atherosclerosis. However, whether mitochondrial DNA synthesis affects macrophage function and atherosclerosis pathology is not fully understood. Here we show, by transcriptomic analyzes of plaque macrophages, spatial single cell transcriptomics of atherosclerotic plaques, and functional experiments, that mitochondrial DNA (mtDNA) synthesis in atherosclerotic plaque macrophages are triggered by vascular cell adhesion molecule 1 (VCAM-1) under inflammatory conditions in both humans and mice. Mechanistically, VCAM-1 activates C/EBPα, which binds to the promoters of key mitochondrial biogenesis genes - Cmpk2 and Pgc1a. Increased CMPK2 and PGC-1α expression triggers mtDNA synthesis, which activates STING-mediated inflammation. Consistently, atherosclerosis and inflammation are less severe in Apoe−/− mice lacking Vcam1 in macrophages. Downregulation of macrophage-specific VCAM-1 in vivo leads to decreased expression of LYZ1 and FCOR, involved in STING signalling. Finally, VCAM-1 expression in human carotid plaque macrophages correlates with necrotic core area, mitochondrial volume, and oxidative damage to DNA. Collectively, our study highlights the importance of macrophage VCAM-1 in inflammation and atherogenesis pathology and proposes a self-acerbating pathway involving increased mtDNA synthesis. Macrophages and their metabolism are known to contribute to inflammation in the atherosclerotic plaques, but the underpinning molecular level regulatory processes are lesser known. Here authors show that under inflammatory conditions, macrophages express VCAM-1 within the atherosclerotic plaques, which leads to increased mitochondrial DNA synthesis via activation of the transcription factor C/EBPα, which in turn triggers inflammation by STING signalling.