Role of Stromelysin 2 (MMP-10) in Lung Immunity

先天性免疫系统在维持健康的肺和形成适应性免疫系统中起着关键作用。 对攻击的免疫反应。对于大多数生物学过程， 炎症由积极和消极因素之间的平衡控制。我们的初步数据 表明基质金属蛋白酶基因家族成员基质溶素-2（MMP-10）的功能是 通过控制浸润的细胞的流入和激活状态来控制肺部炎症的程度。 巨噬细胞响应于毒性损伤或细菌感染，基质溶解素-2表达被诱导， 当野生型小鼠的产量达到峰值时，Mmp 10 +/-小鼠死亡或濒死。的死亡率的差异 野生型和无效小鼠之间的差异与细菌清除的差异无关。相反，MMPW“ 肺组织的炎症比野生型小鼠更严重。此外，来自细胞培养的数据 模型表明，大多数基质溶解素-2的表达是由浸润的巨噬细胞产生的， 与来自感染的野生型小鼠的细胞相比，来自MmpIO小鼠的巨噬细胞表达水平降低的一些 免疫抑制因子，如IL-10。其他模型中的基因表达阵列研究（烟雾） 暴露）表明，基质溶解素-2是激活几种免疫途径所必需的。基于这些 根据这些数据，我们假设基质分解酶-2在调节肺部炎症和免疫反应中起作用。 通过控制浸润的巨噬细胞的活化状态， 免疫过程。为了更详细地研究基质溶解素-2的作用，我们建议1）鉴定基质溶解素-2的表达。 巨噬细胞的亚群和受基质分解素-2影响的活化状态; 2）确定巨噬细胞的相对亚群， 上皮细胞和巨噬细胞来源的基质溶解素-2的作用;和3）评估基质溶解素-2在 控制巨噬细胞对细菌感染的反应。该项目补充了 该计划旨在探索将肺部先天免疫与下游适应性反应联系起来的机制， 并提出了与其他三个项目和两个科学核心的几个相互作用。

The innate immune system plays critical roles in maintaining a healthy lung and in shaping the adaptive immune response to challenge. As for most biological processes, the extent, pattern, and duration of inflammation are controlled by a balance between positive and negative factors. Our preliminary data indicates that stromelysin-2 (MMP-10), a member of the matrix metalloproteinase gene family, functions to govern the extent of inflammation in the lung by controlling the influx and activation state of infiltrated macrophages. In response to toxic injury or bacterial infection, stromelysin-2 expression is induced, and when production peaked in wildtype mice, MmpIO'^' mice died or were moribund. The difference in mortality between wildtype and null mice was not associated with a difference in bacterial clearance. Rather, MmpW'' had more severe inflammation in lung tissue than did wildtype mice. Furthermore, data from cell culture models indicate that most stromelysin-2 expression is produced by infiltrated macrophages, and compared to cells from infected wildtype mice, macrophages from MmpIO''' mice expressed reduced levels of some immunosuppressive factors, such as IL-10. Gene expression arrays studies in other models (smoke exposure) suggest that stromelysin-2 is needed for activation of several immune pathways. Based on these data, we hypothesize that stromelysln-2 functions to moderate lung inflammation and immune processes by controlling the activation state of infiltrated macrophages and, in turn, downstream Immune processes. To study the role of stromelysin-2 in more detail, we propose to 1) identify the subpopulation of macrophages and the activation status affected by stromelysin-2; 2) determine the relative roles of epithelial- and macrophage-derived stromelysin-2; and 3) assess the role of stromelysin-2 in governing the macrophage response to bacterial infection. This project complements the overall theme of this Program to explore mechanisms linking innate immunity in the lung to downstream adaptive responses, and several interactions are proposed with the other three projects and both scientific cores.