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

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 gamma-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.

Automated summary

The study revealed that HDM-AEC-EXOs facilitate recruitment, proliferation, migration, and activation of DCs, with CNTN1 playing a critical role. Notch2 receptor is necessary for relaying the CNTN1 signal to activate TH2 cell/TH17 cell immune response. Studies of patients with asthma support the existence of the CNTN1-Notch2 axis observed in cell and mouse models.