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

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

作者地址："[Do, Danh C.; Zhang, Yan; Tu, Wei; Hu, Xinyue; Huang, Shau-Ku; Gao, Peisong] Johns Hopkins Univ, Sch Med, Div Allergy & Clin Immunol, Baltimore, MD USA; [Zhang, Yan; Hu, Xinyue] Cent South Univ, Xiangya Hosp, Dept Resp Med, Changsha, Hunan, Peoples R China; [Tu, Wei; Liu, Zhigang] Shenzhen Univ, Dept Respirol & Allergy, Affiliated Hosp 3, Shenzhen, Peoples R China; [Xiao, Xiaojun; Liu, Zhigang] Shenzhen Univ, Sch Med, Inst Allergy & Immunol, Shenzhen, Peoples R China; [Chen, Jingsi] Chongqing Med Univ, Childrens Hosp, Chongqing, Peoples R China; [Hao, Haiping] Johns Hopkins Univ, JHMI Deep Sequencing & Microarray Core Facil, Sch Med, Baltimore, MD USA; [Li, Jing] Guangzhou Med Univ, Guangzhou Inst Resp Hlth, Dept Allergy & Clin Immunol, State Key Lab Resp Dis,Affiliated Hosp 1, Guangzhou, Peoples R China; [Huang, Shau-Ku] Natl Hlth Res Inst, Natl Inst Environm Hlth Sci, Miaoli, Taiwan; [Wan, Mei] Johns Hopkins Univ, Dept Orthopaed Surg, Sch Med, Baltimore, MD USA"

通信作者："Gao, PS (corresponding author), Johns Hopkins Asthma & Allergy Ctr, 5501 Hopkins Bayview Circle,Room 3B-71, Baltimore, MD 21224 USA."

来源：JCI INSIGHT

ESI学科分类：CLINICAL MEDICINE

WOS号：WOS:000677560000017

JCR分区：Q1

影响因子：8

年份：2021

卷号：6

期号：14

开始页：　

结束页：　

文献类型：Article

关键词：　

摘要："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;RhoA(ft/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;RhoA(ft/fl) mice showed a significant reduction in Tgf-beta 1 levels in BALF and lung tissues. and administration of recombinant Tgf-beta 1 to the mice rescued Tgf-beta 1 and alleviated the increased allergic airway inflammation observed in Sftpc-cre;RhoA(ft/fl) mice. Using RNA sequencing technology. we identified Slc26a4 (pendrin), a trans membrane 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 (FEV,%). Furthermore, SLC26A4 inhibition promoted epithelial TGF-beta 1 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."

基金机构："US NIHUnited States Department of Health & Human ServicesNational Institutes of Health (NIH) - USA [R56 AI143668, 2R56ES021739, R21 AI137547, R01AI141642, RO1AI153331]; National Natural Science Foundation of ChinaNational Natural Science Foundation of China (NSFC) [U1801286]"

基金资助正文："We thank Michael A. O'Reilly at the University of Rochester Medical Center for providoing Sftpc-cre mice and Yi Zheng at the University of Cincinnati for providing RhoAfl/fl mice for this study. We thank Yingchun Shen for her critical comments on the manuscript. The research was supported by grants from the US NIH (R56 AI143668, 2R56ES021739, R21 AI137547, R01AI141642, and RO1AI153331 to PG) and National Natural Science Foundation of China (U1801286 to JL)."