Macrophage metalloelastase (MMP-12) deficiency mitigates retinal inflammation and pathological angiogenesis in ischemic retinopathy.
Macrophage metalloelastase (MMP-12) deficiency mitigates retinal inflammation and pathological angiogenesis in ischemic retinopathy.
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DOI：
10.1371/journal.pone.0052699
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发表时间：
2012
期刊：
影响因子：
3.7
通讯作者：
Zhang SX
中科院分区：
文献类型：
--
作者：
Li J;Wang JJ;Peng Q;Chen C;Humphrey MB;Heinecke J;Zhang SX
病理性血管生成是导致视网膜缺血性和炎症性疾病视力丧失的主要原因。最近的证据表明，巨噬细胞金属弹性蛋白酶(MMP12)是一种巨噬细胞来源的弹性蛋白水解酶，与炎症、组织重塑和血管生成有关。然而，对基质金属蛋白酶-12在视网膜病理生理学中的作用知之甚少。本研究旨在利用基质金属蛋白酶-12基因敲除(KO)小鼠探讨该酶在氧诱导视网膜病变(OIR)视网膜血管生成中的作用。我们发现基质金属蛋白酶-12在OIR中表达上调，并伴有巨噬细胞浸润和炎性标志物的增加。与野生型小鼠相比，MMP12KO小鼠OIR中黏附分子和炎性细胞因子水平降低，血管渗漏减少。与此同时，这些小鼠的视网膜中巨噬细胞含量显著减少，巨噬细胞迁移能力受损。值得注意的是，基质金属蛋白酶-12的缺失减轻了早期OIR的视网膜毛细血管丢失，并减轻了病理性视网膜新生血管(NV)。在使用MMP408的研究中也观察到了类似的结果，MMP408是一种基质金属蛋白酶-12的药物抑制剂。有趣的是，与减少病理性血管生成相反，缺乏基质金属蛋白酶-12加速了OIR中无血管视网膜的血管重建。综上所述，我们得出结论，基质金属蛋白酶-12是巨噬细胞浸润和炎症的关键调节因子，有助于视网膜血管功能障碍和病理性血管生成。
Pathological angiogenesis is a major cause of vision loss in ischemic and inflammatory retinal diseases. Recent evidence implicates macrophage metalloelastase (MMP-12), a macrophage-derived elastinolytic protease in inflammation, tissue remodeling and angiogenesis. However, little is known about the role of MMP-12 in retinal pathophysiology. The present study aims to explore the enzyme’s contributions to retinal angiogenesis in oxygen-induced retinopathy (OIR) using MMP-12 knockout (KO) mice. We find that MMP-12 expression was upregulated in OIR, accompanied by elevated macrophage infiltration and increased inflammatory markers. Compared to wildtype mice, MMP-12 KO mice had decreased levels of adhesion molecule and inflammatory cytokines and reduced vascular leakage in OIR. Concomitantly, these mice had markedly reduced macrophage content in the retina with impaired macrophage migratory capacity. Significantly, loss of MMP-12 attenuated retinal capillary dropout in early OIR and mitigated pathological retinal neovascularization (NV). Similar results were observed in the study using MMP408, a pharmacological inhibitor of MMP-12. Intriguingly, in contrast to reducing pathological angiogenesis, lack of MMP-12 accelerated revascularization of avascular retina in OIR. Taken together, we conclude that MMP-12 is a key regulator of macrophage infiltration and inflammation, contributing to retinal vascular dysfunction and pathological angiogenesis.