Identification of a novel interleukin-9 receptor complex in non-hematopoietic cells

Beyond cell-cell contact, communication at a distance requires the secretion of cytokines that bind to specific receptors on responsive cells. Interleukin (IL)-9 is a cytokine with pleiotropic effects not only on immune cells that contribute to the progression of tumor and autoimmunity, but also on structural cells including airway and intestinal epithelial cells involved in the development of inflammatory and allergic diseases. Typically, IL-9 receptor (IL-9R) functions as a complex of two subunits – the α-chain (IL-9Rα) and a common γ (γc) chain, that is shared with other cytokine receptors. Although structural cells express IL-9Rα, they lack expression of the γc chain. Thus, it is still unclear how IL-9 transmits a signal through a single IL-9Rα chain in non-hematopoietic cells. This study aimed to explore the possibility that like the type II IL-4Rα, the IL-9Rα chain can pair with the IL-13Rα1 chain, forming a type II IL-9R and can mediate IL-9 responses in epithelial cells. We demonstrated that the IL-9Rα /IL-13Rα1 complex was detected in situ in mouse tracheal epithelial cells and human small airway epithelial cells (SAEC) using proximity ligation assay. STAT3 was activated after exposure to IL-9 in vitro in SAEC when co-cultured with neutralizing antibody targeting γc chain but STAT3 activity returned to its basal level in the presence of anti-IL-13Rα1 antibody, providing further evidence of a type II IL-9R on epithelial cells. Strikingly, asthma-associated genes are upregulated in SAEC upon IL-9 stimulation in RNA-seq analysis. Collectively, our results identify a putative receptor complex - a type II IL-9R composed of IL-9Rα and IL-13Rα1, providing a mechanism for responses of structural cells to IL-9 and a potential role in asthma.