TY - JOUR
T1 - STIM1 is a core trigger of airway smooth muscle remodeling and hyperresponsiveness in asthma
AU - Johnson, Martin T.
AU - Xin, Ping
AU - Cory Benson, J.
AU - Pathak, Trayambak
AU - Walter, Vonn
AU - Emrich, Scott M.
AU - Yoast, Ryan E.
AU - Zhang, Xuexin
AU - Cao, Gaoyuan
AU - Panettieri, Reynold A.
AU - Trebak, Mohamed
N1 - Funding Information:
ACKNOWLEDGMENTS. We thank Drs. Yongsoo Kim and Steffy Manjila for using their vibratome and for help optimizing the conditions for GCaMP experiments, Dr. Han Chen from The Pennsylvania State University College of Medicine Electron Microscopy (EM) facility for assistance with TEM imaging, and Dr. Drew Jones and Mr. Leonard Ash from New York University Langone Health Metabolomics Core Resource Laboratory for assistance with metabolo-mics experiments. We are grateful to the Flow Cytometry and Informatic and Data Analysis Core facilities from The Pennsylvania State University College of Medicine. This work was supported by NIH/National Heart, Lung, and Blood Institute Grants R35-HL150778 (to M.T.), F30-HL147489-01A1 (to M.T.J.), TL1TR002016-04 (to M.T.J.), and P01-HL114471 (to R.A.P).
Publisher Copyright:
© 2022 National Academy of Sciences. All rights reserved.
PY - 2022/1/4
Y1 - 2022/1/4
N2 - 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.
AB - 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.
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U2 - 10.1073/pnas.2114557118
DO - 10.1073/pnas.2114557118
M3 - Article
C2 - 34949717
AN - SCOPUS:85122672326
SN - 0027-8424
VL - 119
JO - Proceedings of the National Academy of Sciences of the United States of America
JF - Proceedings of the National Academy of Sciences of the United States of America
IS - 1
M1 - e2114557118
ER -