Background: While the pathogenesis of asthma is mainly orchestrated by antigen-specific Th2 cells and their cytokines, recent findings indicate the involvement of other subsets of helper T cells and their cytokines. We and others have recently shown that IL-22 has regulatory roles in allergic airway inflammation; however, the underlying mechanisms remain to be determined.
Methods: Airway inflammation was provoked by intratracheal administration of house dust mite (HDM) extract in wild-type (WT) and IL-22-deficient (IL-22-/-) mice, and then evaluated by measuring the number of inflammatory cells in bronchoalveolar lavage fluid (BALF) and cytokine production from T cells. We also analyzed cells that produce IL-22 in the lung in HDM-induced allergic inflammation. In addition, we searched for molecules whose expression is regulated by IL-22 in the lung epithelial cells by RNA-seq analysis. Finally, we evaluated the roles of Reg3γ, one of IL-22-induced genes, in the regulation of HDM-induced allergic airway inflammation.
Results: IL-22-/- mice exhibited significantly enhanced eosinophil, CD4+ T cell, and neutrophil recruitment into BALF, and IL-5, IL-13, and IL-17 production from draining lymph node lymphocytes as compared with WT mice. IL-22 was mainly produced by CD4+ T cells in the lung. IL-22 induced Reg3γ production from lung epithelial cells and that neutralization of Reg3γ significantly exacerbated HDM-induced eosinophilic airway inflammation and Th2 cytokine production. Moreover, exostatin-like 3 (EXTL3), a functional Reg3γ-binding protein, is expressed in lung epithelial cells, and intratracheal administration of recombinant Reg3γ suppressed HDM-induced TSLP and IL-33 expression and accumulation of type 2 innate lymphoid cells in the lung.
Conclusions: IL-22 induces Reg3γ production from lung epithelial cells, and inhibits the development of HDM-induced allergic airway inflammation possibly by inhibiting TSLP and IL-33 production from lung epithelial cells.