J Allergy Clin Immunol. 2021 Dec;148(6):1545-1558.doi: 10.1016/j.jaci.2021.04.025. Epub 2021 May 4.

本文采用的英格恩产品: RNA-Entranster-invivo

Epithelial exosomal contactin-1 promotes monocyte-derived dendritic cell-dominant T-cell responses in asthma

Affiliations

Affiliations

  • 1 Department of Pediatrics, Ruijin Hospital, Shanghai Jiao-tong University School of Medicine, Shanghai, China.
  • 2 Department of Respiratory and Critical Care Medicine, Shanghai Key Discipline for Respiratory Diseases, Institute of Respiratory Diseases, Ruijin Hospital, Shanghai Jiao-tong University School of Medicine, Shanghai, China.
  • 3 School of Medicine and Health Sciences, Department of Biomedical Sciences, University of North Dakota, Grand Forks, ND.
  • 4 Department of Pediatrics, Ruijin Hospital, Shanghai Jiao-tong University School of Medicine, Shanghai, China. Electronic address: xzw10484@rjh.com.cn.

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Abstract

Background: Exosomes have emerged as a vital player in cell-cell communication; however, whether airway epithelial cell (AEC)-generated exosomes participate in asthma development remains unknown.

Objective: Our aims were to characterize the AEC-secreted exosomes and the potentially functional protein(s) that may contribute to the proinflammatory effects of AEC exosomes in the dendritic cell (DC)-dominant airway allergic models and to confirm their clinical significance in patients with asthma.

Methods: Mice were treated with exosomes derived from house dust mite (HDM)-stimulated AECs (HDM-AEC-EXOs) or monocyte-derived DCs primed by HDM and/or contactin-1 (CNTN1). The numbers of DCs in the lung were determined by flow cytometry. Proteomic analysis of purified HDM-AEC-EXOs was performed. CNTN1 small interfering RNA was designed to probe its role in airway allergy, and γ-secretase inhibitor was used to determine involvement of the Notch pathway.

Results: HDM-AEC-EXOs facilitate the recruitment, proliferation, migration, and activation of monocyte-derived DCs in cell culture and in mice. CNTN1 in exosomes is a critical player in asthma pathology. RNA interference-mediated silencing and pharmaceutical inhibitors characterize Notch2 receptor as necessary for relaying the CNTN1 signal to activate TH2 cell/TH17 cell immune response. Studies of patients with asthma also support existence of the CNTN1-Notch2 axis that has been observed in cell and mouse models.

Conclusion: This study’s findings reveal a novel role for CNTN1 in asthma pathogenesis mediated through exosome secretion, indicating a potential strategy for the treatment of allergic airway inflammation.

Keywords: Asthma; Notch2; contactin-1; dendritic cells; epithelial cells; exosomes.

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