TY - JOUR
T1 - TRPC1 intensifies house dust mite-induced airway remodeling by facilitating epithelial-to-mesenchymal transition and STAT3/NF-κB signaling
AU - Pu, Qinqin
AU - Zhao, Yuanyu
AU - Sun, Yuyang
AU - Huang, Ting
AU - Lin, Ping
AU - Zhou, Chuanmin
AU - Qin, Shugang
AU - Singh, Brij B.
AU - Wu, Min
N1 - Funding Information:
The authors thank S. Abrahamson (University of North Dakota Imaging Core Facility) for help with confocal imaging. This work was supported by the U.S. National Institutes of Health (NIH) National Institute of Allergy and Infectious Diseases Grants R01 AI109317-01A1 and AI101973-01, NIH National Institute of Dental and Craniofacial Research Grants R01DE017102 and R01DE022765, as well as an NIH IDeA Networks of Biomedical Research Excellence National Institute of General Medical Sciences (NIGMS) Grant P20GM103442 and Centers of Biomedical Research Excellence (COBRE) NIGMS Grant P20GM113123. The authors declare no conflicts of interest.
PY - 2019/1
Y1 - 2019/1
N2 - Airway remodeling with progressive epithelial alterations in the respiratory tract is a severe consequence of asthma. Although dysfunctional signaling transduction is attributed to airway inflammation, the exact mechanism of airway remodeling remains largely unknown. TRPC1, a member of the transient receptor potential canonical Ca2+ channel family, possesses versatile functions but its role in airway remodeling remains undefined. Here, we show that ablation of TRPC1 in mice alleviates airway remodeling following house dust mite (HDM) challenge withdecreases inmucus production, cytokine secretion, and collagen deposition. HDM challengeinduces Ca2+ influx via the TRPC1 channel, resulting in increased levels of signal transducer and activator of transcription 3 (STAT3) and proinflammatory cytokines. In contrast, STAT3 expression was significantly decreased in TRPC12/2 mouse lungs compared with wild-type controls after HDM challenge. Mechanistically, STAT3 promotes epithelialto-mesenchymal transition and increases mucin 5AC expression. Collectively, these findings identify TRPC1 as a modulator of HDM-induced airway remodeling via STAT3-mediated increase in mucus production, which provide new insight in our understanding of the molecular basis of airway remodeling, and identify novel therapeutic targets for intervention of severe chronic asthma.
AB - Airway remodeling with progressive epithelial alterations in the respiratory tract is a severe consequence of asthma. Although dysfunctional signaling transduction is attributed to airway inflammation, the exact mechanism of airway remodeling remains largely unknown. TRPC1, a member of the transient receptor potential canonical Ca2+ channel family, possesses versatile functions but its role in airway remodeling remains undefined. Here, we show that ablation of TRPC1 in mice alleviates airway remodeling following house dust mite (HDM) challenge withdecreases inmucus production, cytokine secretion, and collagen deposition. HDM challengeinduces Ca2+ influx via the TRPC1 channel, resulting in increased levels of signal transducer and activator of transcription 3 (STAT3) and proinflammatory cytokines. In contrast, STAT3 expression was significantly decreased in TRPC12/2 mouse lungs compared with wild-type controls after HDM challenge. Mechanistically, STAT3 promotes epithelialto-mesenchymal transition and increases mucin 5AC expression. Collectively, these findings identify TRPC1 as a modulator of HDM-induced airway remodeling via STAT3-mediated increase in mucus production, which provide new insight in our understanding of the molecular basis of airway remodeling, and identify novel therapeutic targets for intervention of severe chronic asthma.
KW - Asthma
KW - Cell signaling
KW - Ion channel
KW - Transcription factors
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U2 - 10.1096/fj.201801085R
DO - 10.1096/fj.201801085R
M3 - Article
C2 - 30067380
AN - SCOPUS:85059237357
VL - 33
SP - 1074
EP - 1085
JO - FASEB Journal
JF - FASEB Journal
SN - 0892-6638
IS - 1
ER -