The Presence and Pathogenic Roles of M(IL-33 + IL-2) Macrophages in Allergic Airway Inflammation.

Abstract

Macrophages, one of the most abundant immune cells in the lung, have drawn great attention in allergic asthma. Currently, most studies emphasize alternative activated (M2) polarization bias. However, macrophage function in allergic asthma is still controversial. Interleukin (IL)-9 contributes to the development and pathogenesis of allergic airway inflammation. We sought to investigate the IL-9-producing macrophage and its role in allergic asthma. The model of ovalbumin (OVA)-induced allergic airway inflammation was employed to evaluate IL-9 production in macrophages of lung tissues. We used 22 cytokines or stimuli to screen for IL-9-producing mouse macrophage subset in vitro. Real-time PCR, flow cytometry, ELISA, and RNA-seq to explore the subset. Conditional IL-33 receptor knockout (Lyz-ST2KO) mice and cellular adoptive transfer experiment were used to characterize the potential roles of M(IL-33 + IL-2) in allergic asthma. We identified a unique pathogenic IL-9-producing macrophage in OVA-induced allergic airway inflammation. We found that only IL-33 significantly induced IL-9 production in mouse macrophages, and IL-2 collaborated with IL-33 to promote IL-9 production, referred to as M(IL-33 + IL-2). Importantly, human monocyte-derived macrophages produced IL-9 after IL-33 and IL-2 stimulation. Using Lyz-ST2KO mice and adoptive transfer of M(IL-33 + IL-2), we found that M(IL-33 + IL-2) significantly promoted pathogenesis in OVA-induced allergic airway inflammation. M(IL-33 + IL-2) has a distinctive gene expression profile with high expression of IL-9, IL-5, and IL-13 and its polarization is dependent on JAK2-STAT3-IRF1 pathway. The identification of M(IL-33 + IL-2) subset extends the diversity and heterogeneity of macrophage subsets and may offer novel therapeutic strategies for the treatment of allergic inflammation.