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

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. ChandelJindan Yu, Xiangdong Fu, Irina Petrache, Rubin Tuder, G. R.Scott Budinger*, Jing Liu

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

3 Scopus citations

Abstract

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 B (NF-B) signaling, spontaneously develop progressive age-related changes resembling COPD. Furthermore, loss of Miz1 up-regulates the expression of Ace2, the receptor for SARSCoV-2. Concomitant partial loss of NF-B/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-B–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.

Original languageEnglish (US)
Article numbereabb7238
JournalScience Advances
Volume6
Issue number33
DOIs
StatePublished - Aug 2020

ASJC Scopus subject areas

  • General

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