Epithelial cell-specific loss of function of Miz1 causes a spontaneous COPD-like phenotype and up-regulates Ace2 expression in mice.

Cigarette smoking, the leading cause of chronic obstructive pulmonary disease (COPD), has been implicated as a risk factor for severe disease in patients infected with the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Here we show that mice with lung epithelial cell-specific loss of function of Miz1, which we identified as a negative regulator of nuclear factor κB (NF-κB) signaling, spontaneously develop progressive age-related changes resembling COPD. Furthermore, loss of Miz1 up-regulates the expression of Ace2, the receptor for SARS-CoV-2. Concomitant partial loss of NF-κB/RelA prevented the development of COPD-like phenotype in Miz1-deficient mice. Miz1 protein levels are reduced in the lungs from patients with COPD, and in the lungs of mice exposed to chronic cigarette smoke. Our data suggest that Miz1 down-regulation-induced sustained activation of NF-κB-dependent inflammation in the lung epithelium is sufficient to induce progressive lung and airway destruction that recapitulates features of COPD, with implications for COVID-19. Copyright © 2020 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works. Distributed under a Creative Commons Attribution NonCommercial License 4.0 (CC BY-NC).

Citation

Hanh Chi Do-Umehara, Cong Chen, Qiao Zhang, Alexander V Misharin, Hiam Abdala-Valencia, S Marina Casalino-Matsuda, Paul A Reyfman, Kishore R Anekalla, Francisco J Gonzalez-Gonzalez, Marc A Sala, Chao Peng, Ping Wu, Catherine C L Wong, Ravi Kalhan, Ankit Bharat, Harris Perlman, Karen M Ridge, Jacob I Sznajder, Peter H S Sporn, Navdeep S Chandel, Jindan Yu, Xiangdong Fu, Irina Petrache, Rubin Tuder, G R Scott Budinger, Jing Liu. Epithelial cell-specific loss of function of Miz1 causes a spontaneous COPD-like phenotype and up-regulates Ace2 expression in mice. Science advances. 2020 Aug;6(33):eabb7238

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PMID: 32851183

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