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Activation of ILC2s through constitutive IFNγ signaling reduction leads to spontaneous pulmonary fibrosis

Author

Listed:
  • Natsuko Otaki

    (RIKEN Center for Integrative Medical Sciences (IMS)
    Keio University School of Medicine)

  • Yasutaka Motomura

    (RIKEN Center for Integrative Medical Sciences (IMS)
    Osaka University
    Osaka University)

  • Tommy Terooatea

    (RIKEN Center for Integrative Medical Sciences (IMS))

  • S. Thomas Kelly

    (RIKEN Center for Integrative Medical Sciences (IMS))

  • Miho Mochizuki

    (RIKEN Center for Integrative Medical Sciences (IMS))

  • Natsuki Takeno

    (RIKEN Center for Integrative Medical Sciences (IMS))

  • Shigeo Koyasu

    (Keio University School of Medicine
    RIKEN Center for Integrative Medical Sciences (IMS))

  • Miu Tamamitsu

    (The University of Tokyo)

  • Fuminori Sugihara

    (Osaka University)

  • Junichi Kikuta

    (Osaka University)

  • Hideya Kitamura

    (Kanagawa Cardiovascular and Respiratory Center)

  • Yoshiki Shiraishi

    (Tokai University School of Medicine)

  • Jun Miyanohara

    (Discovery Accelerator, Astellas Pharma Inc.)

  • Yuji Nagano

    (Discovery Accelerator, Astellas Pharma Inc.)

  • Yuji Saita

    (Discovery Accelerator, Astellas Pharma Inc.)

  • Takashi Ogura

    (Kanagawa Cardiovascular and Respiratory Center)

  • Koichiro Asano

    (Tokai University School of Medicine)

  • Aki Minoda

    (RIKEN Center for Integrative Medical Sciences (IMS)
    Radboud University)

  • Kazuyo Moro

    (RIKEN Center for Integrative Medical Sciences (IMS)
    Osaka University
    Osaka University
    Osaka University)

Abstract

Pulmonary fibrosis (PF), a condition characterized by inflammation and collagen deposition in the alveolar interstitium, causes dyspnea and fatal outcomes. Although the bleomycin-induced PF mouse model has improved our understanding of exogenous factor-induced fibrosis, the mechanism governing endogenous factor-induced fibrosis remains unknown. Here, we find that Ifngr1-/-Rag2-/- mice, which lack the critical suppression factor for group 2 innate lymphoid cells (ILC2), develop PF spontaneously. The onset phase of fibrosis includes ILC2 subpopulations with a high Il1rl1 (IL-33 receptor) expression, and fibrosis does not develop in ILC-deficient or IL-33-deficient mice. Although ILC2s are normally localized near bronchioles and blood vessels, ILC2s are increased in fibrotic areas along with IL-33 positive fibroblasts during fibrosis. Co-culture analysis shows that activated-ILC2s directly induce collagen production from fibroblasts. Furthermore, increased IL1RL1 and decreased IFNGR1 expressions are confirmed in ILC2s from individuals with idiopathic PF, highlighting the applicability of Ifngr1-/-Rag2-/- mice as a mouse model for fibrosis research.

Suggested Citation

  • Natsuko Otaki & Yasutaka Motomura & Tommy Terooatea & S. Thomas Kelly & Miho Mochizuki & Natsuki Takeno & Shigeo Koyasu & Miu Tamamitsu & Fuminori Sugihara & Junichi Kikuta & Hideya Kitamura & Yoshiki, 2023. "Activation of ILC2s through constitutive IFNγ signaling reduction leads to spontaneous pulmonary fibrosis," Nature Communications, Nature, vol. 14(1), pages 1-20, December.
    • Handle: RePEc:nat:natcom:v:14:y:2023:i:1:d:10.1038_s41467-023-43336-6
    DOI: 10.1038/s41467-023-43336-6
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    References listed on IDEAS

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