2016年6月21日 訊 /生物谷BIOON/ --研究發現MMP10能夠通過調節巨噬細胞表達其它種類的MMP蛋白從而促進傷口的結痂與癒合，但以上結果是在無菌的傷口實驗中得出的，因此無法涵蓋MMP10在整個巨噬細胞炎症反應中的作用。為了進一步研究這一問題，來自華盛頓大學的William C. Parks課題組進行了深入研究，發現在病原菌感染過程中MMP10能夠通過控制巨噬細胞活化而緩解炎症反應，相關結果發表在最近一期的《Journal of Immunology》雜誌上。
巨噬細胞是免疫系統中重要的效應細胞，他即能夠促進炎症反應，又能夠抑制炎症反應，促進傷口的癒合。巨噬細胞根據其表型與功能的不同可以分為不同的類別，包括經典的M1型與其它的M2型。M1型巨噬細胞由Th1型細胞因子激活，它具有殺傷感染的病原菌的能力；同時，M1型巨噬細胞還能夠釋放其它的炎性因子，例如IL-1beta，IL-12， TNFa。M2型巨噬細胞主要由Th2型細胞因子，例如IL-4、IL-13激活，並釋放抑制炎性反應的因子，例如IL-10。
巨噬細胞的活性受到許多蛋白的調控，其中包括基質金屬蛋白酶家族（MMP）。正常情況下，MMP10並不表達於成年人體或小鼠的各個器官組織，但是，在受到損傷或感染的情況下，MMP10的表達量會有明顯的提高。通過高通量的基因表達譜分析，我們發現MMP10是一列常見的免疫效應基因。
在該研究中首先，作者發現在肺纖維化患者以及受到綠膿桿菌感染的小鼠肺部出現了明顯的MMP10的表達。之後，作者發現這一MMP10表達的上調與小鼠的死亡率存在明顯的反向相關性。
進一步，作者比較了野生型小鼠與MMP缺失突變體小鼠在綠膿桿菌感染過程中的巨噬細胞反映情況。結果顯示，突變體小鼠肺臟中巨噬細胞的積累數量明顯高於野生型小鼠。通過對這些巨噬細胞進行分析，作者發現MMP10大量表達於局部以及浸潤的巨噬細胞中。之後，作者向突變體小鼠體內注入野生型的巨噬細胞，發現這一操作能夠提高小鼠在受到感染之後體重的恢復能力。
之後，作者發現在缺失MMP10的巨噬細胞中CCL2的表達能力發生了明顯的提升，標誌著巨噬細胞的激活。
綜上，作者證明了在病原菌感染過程中MMP10能夠通過控制巨噬細胞活化而緩解炎症反應。(生物谷bioon.com）
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doi: 10.4049/jimmunol.1600502
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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.