Role of MMP10 in Macrophage Activation

 描述（由申请人提供）：这个新项目将探索不同的巨噬细胞亚群如何重塑过量的气道细胞外基质（ECM），以应对肺损伤，感染或过敏原挑战。机制的重点将集中在如何基质分解素-2（MMP 10），细胞外内肽酶的基质金属蛋白酶家族的成员，在细胞自主的方式来控制ECM降解程序的激活，在交替激活的巨噬细胞的功能。关键的初步数据表明，MMP 10在巨噬细胞中被诱导，并起着驱动其从促炎细胞活化状态的作用（即，M1-偏向）到免疫抑制巨噬细胞（即，M2偏置）。M2巨噬细胞被认为具有重塑能力，另外的初步数据表明，MMP 10通过调节具有基质降解活性的其他金属蛋白酶的表达来驱动M2巨噬细胞中有效重塑表型的活化。该项目将测试MMP 10在受伤/感染的组织环境中响应特定刺激而被诱导的假设，并在巨噬细胞上脱落细胞表面蛋白，并且这种蛋白质的丢失启动信号传导以开启M2偏置巨噬细胞中的ECM重塑程序。目的是：1）确定控制巨噬细胞中MMP 10表达的机制以及MMP 10在肺部疾病模型中的作用; 2）鉴定M2巨噬细胞表达的ECM降解蛋白酶; 3）鉴定并验证影响巨噬细胞活化的MMP 10底物。该方法将包括使用遗传定义的小鼠模型，小鼠和人类细胞以及各种分析方法。

 DESCRIPTION (provided by applicant): This new project will explore how distinct subsets of macrophages remodel excess airway extracellular matrix (ECM) that builds up in response to lung injury, infection, or allergen challenge. 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 ECM-degrading programs in alternatively activated 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 drives 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 hypothesis that MMP10 is induced in response to specific stimuli in an injured/infected tissue environment and sheds a cell-surface protein on macrophage and that loss of this protein initiates signaling to turn on ECM-remodeling programs in M2-biased macrophages. The aims are to 1) determine the mechanisms controlling MMP10 expression in macrophages and role of MMP10 in models of lung disease; 2) identity the ECM-degrading proteinases expressed by M2 macrophages; 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 various analytical approaches.