IL-9-dependent interstitial macrophage function in the allergic lung

项目摘要/摘要：IL-9依赖的间质巨噬细胞在过敏性肺中的作用 尽管IL-9在粘膜环境中起着多效性细胞因子的作用，但IL-9反应的细胞谱系是 仍然没有明确的定义。在一项鉴定IL-9反应细胞的深入研究中，我们发现IL-9介导了促过敏反应 通过靶向肺巨噬细胞的活性。IL-9抑制肺泡巨噬细胞扩张促进募集 单核细胞发育成CD11c+/-间质巨噬细胞群。间质巨噬细胞 依赖IL-9的过敏反应所必需的。IL-9影响肺巨噬细胞功能的机制研究 通过诱导Arg1活性。过继转移Arg1+肺巨噬细胞但不能过继转移Arg1-肺巨噬细胞 恢复在Il9r-/-小鼠身上消失的过敏性炎症。同时，IL-9、IL-9R和IL-9R的表达升高 Arg1与哮喘患者的疾病相关。因此，我们的研究揭示了IL-9/巨噬细胞/Arg1轴为 过敏性呼吸道炎症的潜在治疗靶点。在此续订应用程序中，我们将利用 细胞RNA-seq数据集，以进一步定义显示亲过敏功能的间质巨噬细胞群。 我们将确定导致巨噬细胞基因表达变化的IL-9依赖的途径。最后， 我们将确定依赖Arg1的代谢途径如何影响巨噬细胞的内在基因表达。 总之，这些研究将建立对过敏肺中巨噬细胞功能的详细了解 确定可以探索的治疗价值的途径。

PROJECT SUMMARY / ABSTRACT: IL-9-dependent interstitial macrophage function in the allergic lung Despite IL-9 functioning as a pleiotropic cytokine in mucosal environments, the IL-9 responsive cell repertoire is still not well defined. In a thorough study to identify IL-9-responsive cells, we found that IL-9 mediates pro-allergic activities by targeting lung macrophages. IL-9 inhibits alveolar macrophage expansion and promotes recruitment of monocytes that develop into CD11c+/- interstitial macrophage populations. Interstitial macrophages are required for IL-9-dependent allergic responses. Mechanistically, IL-9 affects the function of lung macrophages by inducing Arg1 activity. Adoptive transfer of Arg1+ lung macrophages but not Arg1- lung macrophages can recover allergic inflammation that is lost in Il9r-/- mice. In parallel, the elevated expression of IL-9, IL-9R, and Arg1 is correlated with disease in asthma patients. Thus, our studies uncover an IL-9/macrophage/Arg1 axis as a potential therapeutic target for allergic airway inflammation. In this renewal application we will leverage single cell RNA-seq datasets to further define the interstitial macrophage population that displays pro-allergic function. We will determine the IL-9-dependent pathways that lead to changes in macrophage gene expression. Finally, we will determine how Arg1-dependent metabolic pathways impact intrinsic gene expression in macrophages. Together, these studies will establish a detailed understanding of macrophage function in the allergic lung and identify pathways that can be explored for therapeutic value.