STIM1 is a core trigger of airway smooth muscle remodeling and hyperresponsiveness in asthma

Martin T. Johnson, Ping Xin, J. Cory Benson, Trayambak Pathak, Vonn Walter, Scott M. Emrich, Ryan E. Yoast, Xuexin Zhang, Gaoyuan Cao, Reynold A. Panettieri, Mohamed Trebak

Research output: Contribution to journalArticlepeer-review

21 Scopus citations

Abstract

Airway remodeling and airway hyperresponsiveness are central drivers of asthma severity. Airway remodeling is a structural change involving the dedifferentiation of airway smooth muscle (ASM) cells from a quiescent to a proliferative and secretory phenotype. Here, we show up-regulation of the endoplasmic reticulum Ca2+ sensor stromal-interacting molecule 1 (STIM1) in ASM of asthmatic mice. STIM1 is required for metabolic and transcriptional reprogramming that supports airway remodeling, including ASM proliferation, migration, secretion of cytokines and extracellular matrix, enhanced mitochondrial mass, and increased oxidative phosphorylation and glycolytic flux. Mechanistically, STIM1-mediated Ca2+ influx is critical for the activation of nuclear factor of activated T cells 4 and subsequent interleukin-6 secretion and transcription of pro-remodeling transcription factors, growth factors, surface receptors, and asthma-associated proteins. STIM1 drives airway hyperresponsiveness in asthmatic mice through enhanced frequency and amplitude of ASM cytosolic Ca2+ oscillations. Our data advocates for ASM STIM1 as a target for asthma therapy.

Original languageEnglish (US)
Article numbere2114557118
JournalProceedings of the National Academy of Sciences of the United States of America
Volume119
Issue number1
DOIs
StatePublished - Jan 4 2022

All Science Journal Classification (ASJC) codes

  • General

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