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- Title
Retrotransposons in Werner syndrome-derived macrophages trigger type I interferon-dependent inflammation in an atherosclerosis model.
- Authors
Paul, Sudip Kumar; Oshima, Motohiko; Patil, Ashwini; Sone, Masamitsu; Kato, Hisaya; Maezawa, Yoshiro; Kaneko, Hiyori; Fukuyo, Masaki; Rahmutulla, Bahityar; Ouchi, Yasuo; Tsujimura, Kyoko; Nakanishi, Mahito; Kaneda, Atsushi; Iwama, Atsushi; Yokote, Koutaro; Eto, Koji; Takayama, Naoya
- Abstract
The underlying mechanisms of atherosclerosis, the second leading cause of death among Werner syndrome (WS) patients, are not fully understood. Here, we establish an in vitro co-culture system using macrophages (iMφs), vascular endothelial cells (iVECs), and vascular smooth muscle cells (iVSMCs) derived from induced pluripotent stem cells. In co-culture, WS-iMφs induces endothelial dysfunction in WS-iVECs and characteristics of the synthetic phenotype in WS-iVSMCs. Transcriptomics and open chromatin analysis reveal accelerated activation of type I interferon signaling and reduced chromatin accessibility of several transcriptional binding sites required for cellular homeostasis in WS-iMφs. Furthermore, the H3K9me3 levels show an inverse correlation with retrotransposable elements, and retrotransposable element-derived double-stranded RNA activates the DExH-box helicase 58 (DHX58)-dependent cytoplasmic RNA sensing pathway in WS-iMφs. Conversely, silencing type I interferon signaling in WS-iMφs rescues cell proliferation and suppresses cellular senescence and inflammation. These findings suggest that Mφ-specific inhibition of type I interferon signaling could be targeted to treat atherosclerosis in WS patients. Werner syndrome (WS) is a rare inherited disorder characterized by premature aging and atherosclerosis. Here, the authors mimic atherosclerosis with iPSC-derived macrophages and vascular cells and find that type I IFN signaling triggered by the reactivation of retrotransposable elements in WS macrophages induces vascular dysfunction.
- Subjects
TYPE I interferons; INTERFERON receptors; INDUCED pluripotent stem cells; VASCULAR endothelial cells; RETROTRANSPOSONS; ATHEROSCLEROSIS; VASCULAR smooth muscle
- Publication
Nature Communications, 2024, Vol 15, Issue 1, p1
- ISSN
2041-1723
- Publication type
Article
- DOI
10.1038/s41467-024-48663-w