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

JCI Insight
Danh C DoPeisong Gao

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 percent...Continue Reading

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Datasets Mentioned

BETA
GSE175932

Methods Mentioned

BETA
transfection
PCR
ELISA
flow cytometry
RNA-seq
environmental stress
GTPases
biopsies
bronchoalveolar lavage
genotyping

Software Mentioned

Image Studio Lite
STAR aligner
GraphPad Prism
FlowJo
GraphPad
STAR
Partek Genomic Suite
ImageJ

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