Control of Macrophage Activation in Lung Disease

摘要 这个项目将探索不同的巨噬细胞亚群如何缓解炎症和重建过度。 肺损伤后形成的呼吸道细胞外基质(ECM)。机械论的焦点将集中在 基质分解素-2(MMP10)是细胞外基质金属蛋白酶家族中的一员，它在细胞外信号转导中起着重要的作用。 以细胞自主的方式控制免疫抑制和ECM降解的激活 巨噬细胞中的程序。关键的初步数据表明，MMP10在巨噬细胞和 将它们的激活状态从促炎细胞(即偏向M1)驱动到免疫抑制的功能 巨噬细胞(即偏向M2)。M2巨噬细胞被认为具有重塑能力，并附加 初步数据显示，MMP10促进了一种有效的重塑表型的激活 M2巨噬细胞通过调节其他具有基质降解活性的金属蛋白酶的表达。这 该项目将测试MMP10在巨噬细胞上释放细胞表面蛋白的假设，以及这种损失 蛋白质启动信号，启动M2偏向的免疫调节和ECM重塑程序 巨噬细胞。其目的是1)确定MMP10在调节巨噬细胞活化和 免疫抑制功能在肺纤维化中的作用。2)鉴定MMP10控制的ECM降解蛋白； 3)确定并验证影响巨噬细胞活化的MMP10底物。该方法将包括 使用基因定义的小鼠模型、小鼠和人类细胞以及分析方法。

ABSTRACT This project will explore how distinct subsets of macrophages moderates inflammation and remodel excess airway extracellular matrix (ECM) that builds up in response to lung injury. The mechanistic focus will center on how stromelysin-2 (MMP10), a member of the matrix metalloproteinase family of extracellular endopeptidases, functions in a cell-autonomous manner to control the activation of immunosuppressive and ECM-degrading programs in macrophages. Key preliminary data demonstrate that MMP10 is induced in macrophages and functions to drive their activation status from pro-inflammatory cells (i.e., M1-biased) to immunosuppressive macrophages (i.e., M2-biased). M2 macrophages are considered to be remodeling competent, and additional preliminary data demonstrates that MMP10 promotes the activation of an effective remodeling phenotype in M2 macrophages by regulating the expression of other metalloproteinases with matrix-degrading activity. This project will test the hypotheses that MMP10 sheds a cell-surface protein on macrophage and that loss of this protein initiates signaling to turn on immuno-regulatory and ECM-remodeling programs in M2-biased macrophages. The aims are to 1) determine the role of MMP10 in regulating macrophage activation and immunosuppressive function in lung fibrosis.; 2) identity the ECM-degrading proteinases controlled by MMP10; and 3) identify and validate the MMP10 substrate affecting macrophage activation. The approach will include the use of genetically-defined mouse models, mouse and human cells, and analytical approaches.