The Transcriptional Regulation and Function of IL-9 in Allergic Lung Inflammation and Tumor Growth

Abstract

IL-9 is a pleiotropic cytokine that mediates allergic airway inflammation and lung tumor growth. Th9 cells are the major IL-9 producers. BATF is one of the major IL-9 inducers in Th9 cells. BATF is expressed and functions in multiple T helper subsets, but it only promotes IL-9 in Th9 cells. So far, the mechanisms that control the specificity of BATF in prompting IL-9 expression is unknown. This work identified two pathways that contribute to the specificity of BATF in activating Il9 gene. First, BATF binding partners, including JunB, c-Jun and Bach2 are required to help BATF interact with the Il9 gene. The low expression of those factors in non-Th9 cells limits the binding of BATF to Il9. Second, factors with the capacity to open chromatin that is not active are essential for gene activation. BATF alone is not enough to open the Il9 locus and we found STAT5 is required to open the Il9 in Th9 cells. Overexpression of STAT5 and BATF can switch non-Th9 cells into IL-9 producers, and further promote allergic disease and limit tumor growth. Importantly, in the lung microenvironment, pro-allergic and pro-tumor functions of IL-9 are dependent on lung macrophages. IL-9 alters the heterogeneity of pulmonary macrophage populations and is critical for the induction of a new pulmonary macrophage population under disease states. Loss of IL-9 signaling in lung interstitial macrophages causes decreased allergic inflammation and tumor growth. Mechanistically, IL-9 affects the function of lung macrophage populations by increasing Arginase 1 expression and activity, a protein closely linked to the activity of lung macrophages during inflammation. Thus, this work has uncovered the regulatory mechanism underlying IL-9 production in Th9 cells and also mapped out the downstream targets of IL-9.