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

Author

Listed:
  • Sudip Kumar Paul

    (Chiba University)

  • Motohiko Oshima

    (The University of Tokyo)

  • Ashwini Patil

    (Combinatics Inc.)

  • Masamitsu Sone

    (Chiba University
    Hokkaido 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
    Salk Institute for Biological Studies)

  • 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
    Kyoto University)

  • Naoya Takayama

    (Chiba University)

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.

Suggested Citation

  • Sudip Kumar Paul & Motohiko Oshima & Ashwini Patil & Masamitsu Sone & Hisaya Kato & Yoshiro Maezawa & Hiyori Kaneko & Masaki Fukuyo & Bahityar Rahmutulla & Yasuo Ouchi & Kyoko Tsujimura & Mahito Nakan, 2024. "Retrotransposons in Werner syndrome-derived macrophages trigger type I interferon-dependent inflammation in an atherosclerosis model," Nature Communications, Nature, vol. 15(1), pages 1-17, December.
    • Handle: RePEc:nat:natcom:v:15:y:2024:i:1:d:10.1038_s41467-024-48663-w
    DOI: 10.1038/s41467-024-48663-w
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    References listed on IDEAS

    as
    1. Vera Gorbunova & Andrei Seluanov & Paolo Mita & Wilson McKerrow & David Fenyö & Jef D. Boeke & Sara B. Linker & Fred H. Gage & Jill A. Kreiling & Anna P. Petrashen & Trenton A. Woodham & Jackson R. Ta, 2021. "The role of retrotransposable elements in ageing and age-associated diseases," Nature, Nature, vol. 596(7870), pages 43-53, August.
    2. Marco Cecco & Takahiro Ito & Anna P. Petrashen & Amy E. Elias & Nicholas J. Skvir & Steven W. Criscione & Alberto Caligiana & Greta Brocculi & Emily M. Adney & Jef D. Boeke & Oanh Le & Christian Beaus, 2019. "L1 drives IFN in senescent cells and promotes age-associated inflammation," Nature, Nature, vol. 566(7742), pages 73-78, February.
    3. Jie Wang & Cristina Zibetti & Peng Shang & Srinivasa R. Sripathi & Pingwu Zhang & Marisol Cano & Thanh Hoang & Shuli Xia & Hongkai Ji & Shannath L. Merbs & Donald J. Zack & James T. Handa & Debasish S, 2018. "ATAC-Seq analysis reveals a widespread decrease of chromatin accessibility in age-related macular degeneration," Nature Communications, Nature, vol. 9(1), pages 1-13, December.
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