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Profibrotic function of pulmonary group 2 innate lymphoid cells is controlled by regnase-1

Yoshinari Nakatsuka, Ai Yaku, Tomohiro Handa, Alexis Vandenbon, Yuki Hikichi, Yasutaka Motomura, Ayuko Sato, Masanori Yoshinaga, Kiminobu Tanizawa, Kizuku Watanabe, Toyohiro Hirai, Kazuo Chin, Yutaka Suzuki, Takuya Uehata, Takashi Mino, Tohru Tsujimura, Kazuyo Moro, Osamu Takeuchi
European Respiratory Journal 2021 57: 2000018; DOI: 10.1183/13993003.00018-2020
Yoshinari Nakatsuka
1Dept of Respiratory Care and Sleep Medicine, Graduate School of Medicine, Kyoto University, Kyoto, Japan
2Dept of Medical Chemistry, Graduate School of Medicine, Kyoto University, Kyoto, Japan
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Ai Yaku
2Dept of Medical Chemistry, Graduate School of Medicine, Kyoto University, Kyoto, Japan
3Dept of Rheumatology and Clinical Immunology, Graduate School of Medicine, Kyoto University, Kyoto, Japan
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Tomohiro Handa
4Dept of Advanced Medicine for Respiratory Failure, Graduate School of Medicine, Kyoto University, Kyoto, Japan
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Alexis Vandenbon
5Laboratory of Systems Virology, Dept of Biosystems Science, Institute for Frontier Life and Medical Sciences, Kyoto University, Kyoto, Japan
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Yuki Hikichi
6Laboratory for Innate Immune Systems, RIKEN Center for Integrative Medical Sciences, Kanagawa, Japan
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Yasutaka Motomura
7Dept of Microbiology and Immunology, Osaka University Graduate School of Medicine, Osaka, Japan
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Ayuko Sato
8Dept of Pathology, Hyogo College of Medicine, Hyogo, Japan
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Masanori Yoshinaga
2Dept of Medical Chemistry, Graduate School of Medicine, Kyoto University, Kyoto, Japan
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Kiminobu Tanizawa
9Dept of Respiratory Medicine, Graduate School of Medicine, Kyoto University, Kyoto, Japan
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  • ORCID record for Kiminobu Tanizawa
Kizuku Watanabe
9Dept of Respiratory Medicine, Graduate School of Medicine, Kyoto University, Kyoto, Japan
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Toyohiro Hirai
9Dept of Respiratory Medicine, Graduate School of Medicine, Kyoto University, Kyoto, Japan
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Kazuo Chin
1Dept of Respiratory Care and Sleep Medicine, Graduate School of Medicine, Kyoto University, Kyoto, Japan
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Yutaka Suzuki
10Laboratory of Functional Genomics, Dept of Medical Genome Sciences, Graduate School of Frontier Sciences, The University of Tokyo, Chiba, Japan
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Takuya Uehata
2Dept of Medical Chemistry, Graduate School of Medicine, Kyoto University, Kyoto, Japan
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Takashi Mino
2Dept of Medical Chemistry, Graduate School of Medicine, Kyoto University, Kyoto, Japan
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Tohru Tsujimura
8Dept of Pathology, Hyogo College of Medicine, Hyogo, Japan
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Kazuyo Moro
6Laboratory for Innate Immune Systems, RIKEN Center for Integrative Medical Sciences, Kanagawa, Japan
7Dept of Microbiology and Immunology, Osaka University Graduate School of Medicine, Osaka, Japan
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Osamu Takeuchi
2Dept of Medical Chemistry, Graduate School of Medicine, Kyoto University, Kyoto, Japan
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  • ORCID record for Osamu Takeuchi
  • For correspondence: otake@mfour.med.kyoto-u.ac.jp
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Abstract

Regnase-1 is an RNase critical for post-transcriptional control of pulmonary immune homeostasis in mice by degrading immune-related mRNAs. However, little is known about the cell types Regnase-1 controls in the lung, and its relevance to human pulmonary diseases.

Regnase-1-dependent changes in lung immune cell types were examined by a competitive bone marrow transfer mouse model, and group 2 innate lymphoid cells (ILC2s) were identified. Then the associations between Regnase-1 in ILC2s and human diseases were investigated by transcriptome analysis and a bleomycin-induced pulmonary fibrosis mouse model. The clinical significance of Regnase-1 in ILC2s was further assessed using patient-derived cells.

Regnase-1-deficiency resulted in the spontaneous proliferation and activation of ILC2s in the lung. Intriguingly, genes associated with pulmonary fibrosis were highly upregulated in Regnase-1-deficient ILC2s compared with wild-type, and supplementation of Regnase-1-deficient ILC2s augmented bleomycin-induced pulmonary fibrosis in mice. Regnase-1 suppresses mRNAs encoding transcription factors Gata3 and Egr1, which are potent to regulate fibrosis-associated genes. Clinically, Regnase-1 protein levels in ILC2 negatively correlated with the ILC2 population in bronchoalveolar lavage fluid. Furthermore, idiopathic pulmonary fibrosis (IPF) patients with ILC2s >1500 cells·mL−1 peripheral blood exhibited poorer prognosis than patients with lower numbers, implying the contribution of Regnase-1 in ILC2s for the progression of IPF.

Collectively, Regnase-1 was identified as a critical post-transcriptional regulator of the profibrotic function of ILC2s both in mouse and human, suggesting that Regnase-1 may be a novel therapeutic target for IPF.

Abstract

Regnase-1 controls the proliferation and activation of ILC2, which thereby attenuates lung fibrosis in mice. In humans, lower regnase-1 level correlates with more abundant ILC2 number, which potentially associates with the prognosis of IPF patients. https://bit.ly/3c3GhKo

Footnotes

  • This article has an editorial commentary: https://doi.org/10.1183/13993003.04029-2020

  • This article has supplementary material available from erj.ersjournals.com

  • Author contributions: Y. Nakatsuka and O. Takeuchi developed the study concept and design. Y. Nakatsuka performed the majority of experiments, clinical data collection and analysis of data. A. Yaku, Y. Hikichi and Y. Motomura also developed experimental design and performed experiments. M. Yoshinaga, T. Uehata and T. Mino helped with the experiments. A. Vandenbon and Y. Suzuki performed data analysis. A. Sato and T. Tsujimura performed histological analysis. T. Handa supervised clinical study. K. Tanizawa, K. Watanabe, T. Hirai and K. Chin performed clinical data collection and helped with clinical data analysis. K. Moro helped with the development of study concept and experimental design, and provided critical materials. Y. Nakatsuka, T. Handa and O. Takeuchi wrote the manuscript. O. Takeuchi led the whole project.

  • Conflict of interest: Y. Nakatsuka reports that the Dept of Respiratory Care and Sleep Control Medicine is funded by endowments from Philips-Respironics, ResMed, Fukuda Denshi and Fukuda Lifetec-Keiji to Kyoto University.

  • Conflict of interest: A. Yaku has nothing to disclose.

  • Conflict of interest: T. Handa has nothing to disclose.

  • Conflict of interest: A. Vandenbon has nothing to disclose.

  • Conflict of interest: Y. Hikichi has nothing to disclose.

  • Conflict of interest: Y. Motomura has nothing to disclose.

  • Conflict of interest: A. Sato has nothing to disclose.

  • Conflict of interest: M. Yoshinaga has nothing to disclose.

  • Conflict of interest: K. Tanizawa has nothing to disclose.

  • Conflict of interest: K. Watanabe has nothing to disclose.

  • Conflict of interest: T. Hirai has nothing to disclose.

  • Conflict of interest: K. Chin reports that the Dept of Respiratory Care and Sleep Control Medicine is funded by endowments from Philips-Respironics, ResMed, Fukuda Denshi and Fukuda Lifetec-Keiji to Kyoto University.

  • Conflict of interest: Y. Suzuki has nothing to disclose.

  • Conflict of interest: T. Uehata has nothing to disclose.

  • Conflict of interest: T. Mino has nothing to disclose.

  • Conflict of interest: T. Tsujimura has nothing to disclose.

  • Conflict of interest: K. Moro has nothing to disclose.

  • Conflict of interest: O. Takeuchi has nothing to disclose.

  • Support statement: This research was supported by a Grant-in-Aid for Scientific Research (S) (18H05278, to O. Takeuchi), Grant-in-Aid for Scientific Research (C) (26461187, to T. Handa), Grant-in-Aid from the Japan Society for the Promotion of Science Grant-in-Aid for Research Activity start-up (18H06221, to Y. Nakatsuka), and Grant-in-Aid for Scientific Research on Innovative Areas “Genome Science” (221S0002, 16H06279 to T. Mino). This research was also supported by AMED under Grant Number JP19gm4010002 (to O. Takeuchi). Funding information for this article has been deposited with the Crossref Funder Registry.

  • Received January 9, 2020.
  • Accepted September 11, 2020.
  • Copyright ©ERS 2021
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Profibrotic function of pulmonary group 2 innate lymphoid cells is controlled by regnase-1
Yoshinari Nakatsuka, Ai Yaku, Tomohiro Handa, Alexis Vandenbon, Yuki Hikichi, Yasutaka Motomura, Ayuko Sato, Masanori Yoshinaga, Kiminobu Tanizawa, Kizuku Watanabe, Toyohiro Hirai, Kazuo Chin, Yutaka Suzuki, Takuya Uehata, Takashi Mino, Tohru Tsujimura, Kazuyo Moro, Osamu Takeuchi
European Respiratory Journal Mar 2021, 57 (3) 2000018; DOI: 10.1183/13993003.00018-2020

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Profibrotic function of pulmonary group 2 innate lymphoid cells is controlled by regnase-1
Yoshinari Nakatsuka, Ai Yaku, Tomohiro Handa, Alexis Vandenbon, Yuki Hikichi, Yasutaka Motomura, Ayuko Sato, Masanori Yoshinaga, Kiminobu Tanizawa, Kizuku Watanabe, Toyohiro Hirai, Kazuo Chin, Yutaka Suzuki, Takuya Uehata, Takashi Mino, Tohru Tsujimura, Kazuyo Moro, Osamu Takeuchi
European Respiratory Journal Mar 2021, 57 (3) 2000018; DOI: 10.1183/13993003.00018-2020
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