2. Academic Validation
  3. Low temperature reduces occludin expression in bronchial epithelial cells: Implications in cold-induced asthma

Low temperature reduces occludin expression in bronchial epithelial cells: Implications in cold-induced asthma

  • Mol Immunol. 2023 Apr 10;157:176-185. doi: 10.1016/j.molimm.2023.03.018.
Tingyang Zhou 1,  Wenjing Liao 1,  Xiaofen Wang 1,  Yiyan Wang 1,  Pingchang Yang 2,  Li Zuo 3,  Xiaowen Zhang 4
Affiliations

Affiliations

  • 1 State Key Laboratory of Respiratory Disease, Department of Otolaryngology, Head & Neck Surgery, Laboratory of ENT-HNS Disease, First Affiliated Hospital of Guangzhou Medical University, Guangzhou, China.
  • 2 State Key Laboratory of Respiratory Disease, Department of Otolaryngology, Head & Neck Surgery, Laboratory of ENT-HNS Disease, First Affiliated Hospital of Guangzhou Medical University, Guangzhou, China; Department of Allergy and Clinical Immunology, The First Affiliated Hospital, Guangzhou Medical University, Guangzhou, China; Research Center of Allergy & Immunology, Shenzhen University School of Medicine, Shenzhen, China.
  • 3 School of Medicine, The University of Texas and UT Health Rio Grande Valley, TX 78539, USA.
  • 4 State Key Laboratory of Respiratory Disease, Department of Otolaryngology, Head & Neck Surgery, Laboratory of ENT-HNS Disease, First Affiliated Hospital of Guangzhou Medical University, Guangzhou, China; Department of Cancer, The First Affiliated Hospital, Guangzhou Medical University, Guangzhou, China; Innovation and Transformation Platform of Upper Airway Disease in Guangdong Province, China; Department of Allergy and Clinical Immunology, The First Affiliated Hospital, Guangzhou Medical University, Guangzhou, China. Electronic address: [email protected].
PMID: 37044043 DOI: 10.1016/j.molimm.2023.03.018
Abstract

Background: Cold exposure is a common factor to trigger asthma attacks. However, the underlying mechanism has not been thoroughly elucidated. We aimed to investigate the hypothesis that low temperature reduces occludin expression and compromises epithelial barrier function in airways, which in turn, results in asthma exacerbation.

Methods: We examined occludin expression in human bronchial epithelial cell line (Beas-2B) cells exposed to either 29 °C or 37 °C. The following drugs were administered prior to cold treatment: MG132 (a Proteasome Inhibitor), cycloheximide (a protein synthesis inhibitor), HC-067047 plus GSK2193874 (transient receptor potential vanilloid 4 [TRPV4] antagonists), or C4-ceramide (a glucocorticoid-inducible kinase [SGK1] activator). siNedd4-2 was transfected into Beas-2B cells to investigate the role that Nedd4-2 plays in mediating occludin instability induced by cold. In animal experiments, we treated ovalbumin (OVA)-induced asthmatic mice with a thermoneutral temperature of 30 °C or cold exposure (10 °C, 6 h/day) for 2 weeks. GSK2193874 or C4-ceramide was administered during the cold treatment. Occludin expression of the lung, pulmonary permeability, serum IgE levels, and lung inflammation were assessed.

Results: Low temperature treatment (29 °C) significantly reduced the expression of occludin in Beas-2B cells from 1 to 9 h, which was rescued upon treatment with MG132, HC-067047 plus GSK2193874, C4-ceramide, or Nedd4-2 knockdown. Low temperatures affected occludin stability through SGK1/Nedd4-2-dependent proteolysis. In vivo mice data revealed that cold exposure compromised the airway epithelial barrier function, decreased occludin expression, and exacerbated lung inflammation, which was attenuated by the GSK2193874 or C4-ceramide injection.

Conclusion: We identified a potential mechanism underlying cold-induced asthma exacerbation involving Nedd4-2-mediated occludin proteolysis and airway epithelial barrier disruption.

Keywords

Airway epithelial barrier; Mouse; Nedd4–2; SGK1; Tight junction protein.

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