@article {Nakatsuka2000018, author = {Yoshinari Nakatsuka and Ai Yaku and Tomohiro Handa and Alexis Vandenbon and Yuki Hikichi and Yasutaka Motomura and Ayuko Sato and Masanori Yoshinaga and Kiminobu Tanizawa and Kizuku Watanabe and Toyohiro Hirai and Kazuo Chin and Yutaka Suzuki and Takuya Uehata and Takashi Mino and Tohru Tsujimura and Kazuyo Moro and Osamu Takeuchi}, title = {Profibrotic function of pulmonary group 2 innate lymphoid cells is controlled by Regnase-1}, elocation-id = {2000018}, year = {2020}, doi = {10.1183/13993003.00018-2020}, publisher = {European Respiratory Society}, abstract = {Regnase-1 is an RNase critical for posttranscriptional 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 patients-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 Regnase1-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 (BAL) fluid. Furthermore, idiopathic pulmonary fibrosis (IPF) patients with more than 1500 cells{\textperiodcentered}mL-1 peripheral blood ILC2s 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 posttranscriptional regulator of the pro-fibrotic function of ILC2s both in mouse and human, suggesting that Regnase-1 may be a novel therapeutic target for IPF.FootnotesThis manuscript has recently been accepted for publication in the European Respiratory Journal. It is published here in its accepted form prior to copyediting and typesetting by our production team. After these production processes are complete and the authors have approved the resulting proofs, the article will move to the latest issue of the ERJ online. Please open or download the PDF to view this article.Conflict of interest: Dr. Nakatsuka reports that The Department 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: Dr. Yaku has nothing to disclose.Conflict of interest: Dr. Handa has nothing to disclose.Conflict of interest: Dr. Vandenbon has nothing to disclose.Conflict of interest: Dr. Hikichi has nothing to disclose.Conflict of interest: Dr. Motomura has nothing to disclose.Conflict of interest: Dr. Sato has nothing to disclose.Conflict of interest: Dr. Yoshinaga has nothing to disclose.Conflict of interest: Dr. Tanizawa has nothing to disclose.Conflict of interest: Dr. Watanabe has nothing to disclose.Conflict of interest: Dr. Hirai has nothing to disclose.Conflict of interest: Dr. Chin reports that The Department 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: Dr. Suzuki has nothing to disclose.Conflict of interest: Dr. Uehata has nothing to disclose.Conflict of interest: Dr. Mino has nothing to disclose.Conflict of interest: Dr. Tsujimura has nothing to disclose.Conflict of interest: Dr. Moro has nothing to disclose.Conflict of interest: Dr. Takeuchi has nothing to disclose.}, issn = {0903-1936}, URL = {https://erj.ersjournals.com/content/early/2020/09/17/13993003.00018-2020}, eprint = {https://erj.ersjournals.com/content/early/2020/09/17/13993003.00018-2020.full.pdf}, journal = {European Respiratory Journal} }