Department of Microbiology and Immunology, Indiana University School of Medicine, Indianapolis, IN 46202, USA.
Department of Pediatrics and Herman B Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, IN 46202, USA.
Sci Immunol. 2022 Feb 18;7(68):eabi9768. doi: 10.1126/sciimmunol.abi9768.
Despite IL-9 functioning as a pleiotropic cytokine in mucosal environments, the IL-9-responsive cell repertoire is still not well defined. Here, we found that IL-9 mediates proallergic activities in the lungs by targeting lung macrophages. IL-9 inhibits alveolar macrophage expansion and promotes recruitment of monocytes that develop into CD11c and CD11c interstitial macrophage populations. Interstitial macrophages were required for IL-9-dependent allergic responses. Mechanistically, IL-9 affected the function of lung macrophages by inducing Arg1 activity. Compared with Arg1-deficient lung macrophages, Arg1-expressing macrophages expressed greater amounts of CCL5. Adoptive transfer of Arg1 lung macrophages but not Arg1 lung macrophages promoted allergic inflammation that mice were protected against. In parallel, the elevated expression of IL-9, IL-9R, Arg1, and CCL5 was correlated with disease in patients with asthma. Thus, our study uncovers an IL-9/macrophage/Arg1 axis as a potential therapeutic target for allergic airway inflammation.
尽管白细胞介素 9 (IL-9) 在黏膜环境中作为一种多效细胞因子发挥作用，但 IL-9 反应细胞谱仍未得到很好的定义。在这里，我们发现 IL-9 通过靶向肺巨噬细胞在肺部介导过敏反应。IL-9 抑制肺泡巨噬细胞的扩增，并促进单核细胞的募集，这些单核细胞分化为 CD11c 和 CD11c 间质巨噬细胞群。间质巨噬细胞是 IL-9 依赖性过敏反应所必需的。在机制上，IL-9 通过诱导 Arg1 活性来影响肺巨噬细胞的功能。与 Arg1 缺陷型肺巨噬细胞相比，表达 Arg1 的巨噬细胞表达了更多的 CCL5。过继转移表达 Arg1 的肺巨噬细胞而非 Arg1 肺巨噬细胞促进了过敏炎症，而过敏炎症使小鼠得到了保护。同时，哮喘患者的 IL-9、IL-9R、Arg1 和 CCL5 的表达升高与疾病相关。因此，我们的研究揭示了 IL-9/巨噬细胞/Arg1 轴作为治疗过敏性气道炎症的潜在靶点。
