Type II alveolar epithelial cell–specific loss of RhoA exacerbates allergic airway inflammation through SLC26A4

Danh C. Do, Yan Zhang, Wei Tu, Xinyue Hu, Xiaojun Xiao, Jingsi Chen, Haiping Hao, Zhigang Liu, Jing Li, Shau Ku Huang, Mei Wan, Peisong Gao

Research output: Contribution to journalArticlepeer-review

1 Citation (Scopus)

Abstract

The small GTPase RhoA and its downstream effectors are critical regulators in the pathophysiological processes of asthma. The underlying mechanism, however, remains undetermined. Here, we generated an asthma mouse model with RhoA–conditional KO mice (Sftpc-cre;RhoAfl/fl) in type II alveolar epithelial cells (AT2) and demonstrated that AT2 cell–specific deletion of RhoA leads to exacerbation of allergen-induced airway hyperresponsiveness and airway inflammation with elevated Th2 cytokines in bronchoalveolar lavage fluid (BALF). Notably, Sftpc-cre;RhoAfl/fl mice showed a significant reduction in Tgf-β1 levels in BALF and lung tissues, and administration of recombinant Tgf-β1 to the mice rescued Tgf-β1 and alleviated the increased allergic airway inflammation observed in Sftpc-cre;RhoAfl/fl mice. Using RNA sequencing technology, we identified Slc26a4 (pendrin), a transmembrane anion exchange, as the most upregulated gene in RhoA-deficient AT2 cells. The upregulation of SLC26A4 was further confirmed in AT2 cells of asthmatic patients and mouse models and in human airway epithelial cells expressing dominant-negative RHOA (RHOA-N19). SLA26A4 was also elevated in serum from asthmatic patients and negatively associated with the percentage of forced expiratory volume in 1 second (FEV1%). Furthermore, SLC26A4 inhibition promoted epithelial TGF-β1 release and attenuated allergic airway inflammation. Our study reveals a RhoA/SLC26A4 axis in AT2 cells that functions as a protective mechanism against allergic airway inflammation.

Original languageEnglish
Article numbere148147
JournalJCI insight
Volume6
Issue number14
DOIs
Publication statusPublished - Jul 22 2021
Externally publishedYes

ASJC Scopus subject areas

  • Medicine(all)

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