A novel regulatory role of the Rab27 effector exophilin5 in allergic airway inflammation
Allergic asthma is a chronic inflammatory airway disease, and its incidence is steadily increasing. The most common treatment is topical inhaled corticosteroid application which, while effective, is only temporarily effective and do not provide a cure for asthma. To move towards a cure, we must better understand the underlying pathophysiology of this process.
In the current study, we clarified that exophilin-5, a Rab27 binding protein, was predominantly expressed in both the major IL-33 producers, lung epithelial cells, and the specialized IL-5 and IL-13 producers in pathogenic Th2 cell population in mice. Exophilin-5 deficiency increased IL-33 secretion of lung epithelial cells as well as IL-5 and IL-13 production from a specific subset of pathogenic Th2 cells that expresses a high level of IL-33 receptor, which resulted in exacerbation of allergic airway inflammation in a mouse model of asthma. Mechanistically, exophilin-5 regulates IL-33 release by keeping epithelial cell integrity and IL-33-depedent overactivation of pathogenic Th2 cells by controlling intracellular traffic of Nox2-containing vesicles. This is the first report to establish the significance of exophilin-5 in the exacerbation of allergic airway inflammation, and provides new insights into the pathophysiology of asthma. (Okunishi K, et al., J. Clin. Invest. 2020). [Epub ahead of print]
2020/05/03