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

Natsuko Otaki, Yasutaka Motomura, Tommy Terooatea, S. Thomas Kelly, Miho Mochizuki, Natsuki Takeno, Shigeo Koyasu, Miu Tamamitsu, Fuminori Sugihara, Junichi Kikuta, Hideya Kitamura, Yoshiki Shiraishi, Jun Miyanohara, Yuji Nagano, Yuji Saita, Takashi Ogura, Koichiro Asano, Aki Minoda and Kazuyo Moro ()
Additional contact information
Natsuko Otaki: RIKEN Center for Integrative Medical Sciences (IMS)
Yasutaka Motomura: RIKEN Center for Integrative Medical Sciences (IMS)
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
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)
Kazuyo Moro: RIKEN Center for Integrative Medical Sciences (IMS)

Nature Communications, 2023, vol. 14, issue 1, 1-20

Abstract: 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.

Date: 2023
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DOI: 10.1038/s41467-023-43336-6

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