Retrotransposons in Werner syndrome-derived macrophages trigger type I interferon-dependent inflammation in an atherosclerosis model

Sudip Kumar Paul, Motohiko Oshima, Ashwini Patil, Masamitsu Sone, Hisaya Kato, Yoshiro Maezawa, Hiyori Kaneko, Masaki Fukuyo, Bahityar Rahmutulla, Yasuo Ouchi, Kyoko Tsujimura, Mahito Nakanishi, Atsushi Kaneda, Atsushi Iwama, Koutaro Yokote (), Koji Eto () and Naoya Takayama ()
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Sudip Kumar Paul: Chiba University
Motohiko Oshima: The University of Tokyo
Ashwini Patil: Combinatics Inc.
Masamitsu Sone: Chiba University
Hisaya Kato: Chiba University
Yoshiro Maezawa: Chiba University
Hiyori Kaneko: Chiba University
Masaki Fukuyo: Chiba University
Bahityar Rahmutulla: Chiba University
Yasuo Ouchi: Chiba University
Kyoko Tsujimura: Chiba University
Mahito Nakanishi: Inc.
Atsushi Kaneda: Chiba University
Atsushi Iwama: The University of Tokyo
Koutaro Yokote: Chiba University
Koji Eto: Chiba University
Naoya Takayama: Chiba University

Nature Communications, 2024, vol. 15, issue 1, 1-17

Abstract: 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.

Date: 2024
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DOI: 10.1038/s41467-024-48663-w

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