MMP10 Control of Macrophage Activation in COPD

描述（由申请人提供）：先天免疫系统在维持健康的肺部和形成对挑战的反应中起着关键作用。就大多数生物过程而言，炎症的程度、模式、持续时间和后果是由积极因素和消极因素之间的平衡控制的。我们的初步数据表明基质金属蛋白酶家族成员基质金属蛋白酶-2 （MMP10）控制浸润性巨噬细胞的内流和激活状态，并在香烟烟雾诱导的肺损伤中发挥多种作用。一方面，它可以调节炎症的程度，特别是浸润性巨噬细胞的内流和激活状态。另一方面，MMP10促进肺泡破坏。我们认为这些表型是由于巨噬细胞活化的差异。具体来说，我们假设MMP10调节巨噬细胞向M1表型（经典活化；促炎）的激活，从而促进更多M2（选择性活化或抗炎）巨噬细胞的分化。M2巨噬细胞，已知在吸烟者的肺部过度代表，被认为是修复和介导基质重塑。然而，随着持续的炎症，修复表型会导致过度的重塑和组织破坏。因此，我们进一步假设，通过促进M2巨噬细胞的分化，MMP10直接或间接地促进了肺气肿的发展。为了更详细地研究MMP10在肺泡破坏中的作用，我们建议：1)确定MMP10在塑造巨噬细胞分化中的作用；2)确定上皮和巨噬细胞来源的MMP10的相对作用；3)评估MMP10在控制巨噬细胞对细菌感染的反应中的作用。

DESCRIPTION (provided by applicant): The innate immune system plays critical roles in maintaining a healthy lung and in shaping the responses to challenge. As for most biological processes, the extent, pattern, duration, and consequence of inflammation are controlled by a balance between positive and negative factors. Our preliminary data indicates that stromelysin-2 (MMP10), a member of the matrix metalloproteinase gene family, functions to govern the influx and activation state of infiltrated macrophages and has diverse roles in cigarette smoke-induced lung damage. On one hand, it moderates the extent of inflammation, particularly, the influx and activation state of infiltrated macrophages. On the other, MMP10 promotes alveolar destruction. We propose that these phenotypes are due to differences in macrophage activation. Specifically, we hypothesize that MMP10 moderates macrophage activation towards an M1 phenotype (classically activated; proinflammatory), thereby promoting the differentiation of more M2 (alternatively activated or anti-inflammatory) macrophages. M2 macrophages, which are known to over-represented in the lungs of smokers, are considered to be reparative and to mediate matrix remodeling. However, with sustained inflammation, a reparative phenotype would lead excessive remodeling and tissue destruction. Hence, we further hypothesize that by promoting the differentiation of M2 macrophages, MMP10 contributes-directly or indirectly-to development of emphysema. To study the role of MMP10 in alveolar destruction more detail, we propose to 1) determine the role of MMP10 in shaping macrophage differentiation; 2) determine the relative roles of epithelial- and macrophage-derived MMP10; and 3) assess the role of MMP10 in governing the macrophage response to bacterial infection. PUBLIC HEALTH RELEVANCE: These studies will characterize a novel, fundamental mechanism controlling macrophage activation and tissue destruction in COPD. Knowledge from this work may provide an effective strategy to limit inflammation-associated damage not only in lung, but in all tissues.