2016年6月21日 讯 /生物谷BIOON/ --研究发现MMP10能够通过调节巨噬细胞表达其它种类的MMP蛋白从而促进伤口的结痂与愈合，但以上结果是在无菌的伤口实验中得出的，因此无法涵盖MMP10在整个巨噬细胞炎症反应中的作用。为了进一步研究这一问题，来自华盛顿大学的William C. Parks课题组进行了深入研究，发现在病原菌感染过程中MMP10能够通过控制巨噬细胞活化而缓解炎症反应，相关结果发表在最近一期的《Journal of Immunology》杂志上。
巨噬细胞是免疫系统中重要的效应细胞，他即能够促进炎症反应，又能够抑制炎症反应，促进伤口的愈合。巨噬细胞根据其表型与功能的不同可以分为不同的类别，包括经典的M1型与其它的M2型。M1型巨噬细胞由Th1型细胞因子激活，它具有杀伤感染的病原菌的能力；同时，M1型巨噬细胞还能够释放其它的炎性因子，例如IL-1beta，IL-12， TNFa。M2型巨噬细胞主要由Th2型细胞因子，例如IL-4、IL-13激活，并释放抑制炎性反应的因子，例如IL-10。
巨噬细胞的活性受到许多蛋白的调控，其中包括基质金属蛋白酶家族（MMP）。正常情况下，MMP10并不表达于成年人体或小鼠的各个器官组织，但是，在受到损伤或感染的情况下，MMP10的表达量会有明显的提高。通过高通量的基因表达谱分析，我们发现MMP10是一列常见的免疫效应基因。
在该研究中首先，作者发现在肺纤维化患者以及受到绿脓杆菌感染的小鼠肺部出现了明显的MMP10的表达。之后，作者发现这一MMP10表达的上调与小鼠的死亡率存在明显的反向相关性。
进一步，作者比较了野生型小鼠与MMP缺失突变体小鼠在绿脓杆菌感染过程中的巨噬细胞反映情况。结果显示，突变体小鼠肺脏中巨噬细胞的积累数量明显高于野生型小鼠。通过对这些巨噬细胞进行分析，作者发现MMP10大量表达于局部以及浸润的巨噬细胞中。之后，作者向突变体小鼠体内注入野生型的巨噬细胞，发现这一操作能够提高小鼠在受到感染之后体重的恢复能力。
之后，作者发现在缺失MMP10的巨噬细胞中CCL2的表达能力发生了明显的提升，标志着巨噬细胞的激活。
综上，作者证明了在病原菌感染过程中MMP10能够通过控制巨噬细胞活化而缓解炎症反应。
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Stromelysin-2 (MMP10) Moderates Inflammation by Controlling Macrophage Activation
Ryan S. McMahan, Timothy P. Birkland, Kate S. Smigiel, Tyler C. Vandivort, Maryam G. Rohani, Anne M. Manicone, John K. McGuire, Sina A. Gharib and William C. Parks
Several members of the matrix metalloproteinase (MMP) family control a range of immune processes, such as leukocyte influx and chemokine activity. Stromelysin-2 (MMP10) is expressed by macrophages in numerous tissues after injury; however, little is known of its function. In this study, we report that MMP10 is expressed by macrophages in human lungs from patients with cystic fibrosis and induced in mouse macrophages in response to Pseudomonas aeruginosa infection both in vivo and by isolated resident alveolar and bone marrow-derived macrophages (BMDM). Our data indicates that macrophage MMP10 serves a beneficial function in response to acute infection. Whereas wild-type mice survived infection with minimal morbidity, 50% of Mmp10?/? mice died and all showed sustained weight loss (morbidity). Although bacterial clearance and neutrophil influx did not differ between genotypes, macrophage numbers were ?3-fold greater in infected Mmp10?/? lungs than in wild-types. Adoptive transfer of wild-type BMDM normalized infection-induced morbidity in Mmp10?/? recipients to wild-type levels, demonstrating that the protective effect of MMP10 was due to its production by macrophages. Both in vivo and in cultured alveolar macrophages and BMDM, expression of several M1 macrophage markers was elevated, whereas M2 markers were reduced in Mmp10?/? tissue and cells. Global gene expression analysis revealed that infection-mediated transcriptional changes persisted in Mmp10?/? BMDM long after they were downregulated in wild-type cells. These results indicate that MMP10 serves a beneficial role in response to acute infection by moderating the proinflammatory response of resident and infiltrating macrophages.