Persistent Inflammation Subverts Thrombospondin-1-Induced Regulation of Retinal Angiogenesis and Is Driven by CCR2 Ligation
Persistent Inflammation Subverts Thrombospondin-1-Induced Regulation of Retinal Angiogenesis and Is Driven by CCR2 Ligation
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DOI：
10.1016/j.ajpath.2011.09.020
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发表时间：
2012-01-01
影响因子：
6
通讯作者：
Xu, Heping
中科院分区：
文献类型：
--
作者：
Chen, Mei;Copland, David A.;Xu, Heping
新生血管性视网膜疾病是炎症反应导致失明的主要原因。虽然非感染性葡萄膜视网膜炎是由CD4(+)T细胞介导的，但在疾病的持续期，可以观察到血管生成反应，伴随着视网膜的退化。完整的临床表现依赖于髓系细胞，这些细胞在表型上与老年性黄斑变性不同，但可能具有共同的效应反应。为了探讨炎症介导的血管生成，我们研究了实验性自身免疫性葡萄膜视网膜炎，这是一种人类葡萄膜炎的动物模型。在严重炎症的最初急性期后，视网膜持续低度炎症，组织浸润性白细胞超过4个月。在这个持续期，血管生成是视网膜新生血管膜，由炎症的小静脉和毛细血管后小静脉形成，随着疾病的进展而增大，并与渗入的精氨酸酶-1(+)巨噬细胞相关。在没有血栓反应蛋白-1的情况下，视网膜新生血管膜显著增加，并与精氨酸酶-1(-)CD68(+)巨噬细胞相关，而趋化因子受体CCR2的缺失导致视网膜新生血管膜减少，并伴有主要的中性粒细胞浸润。CCR2在实验性自身免疫性葡萄膜视网膜炎的视网膜巨噬细胞募集中起重要作用，并以持续性血管生成反应的形式促进慢性化，而血管生成反应又受血管生成抑制物如血栓反应蛋白-1的结构性表达调节。该模型为剖析炎症诱导的眼血管生成的分子和细胞病理学提供了新的平台。(Am J.Pathol2012,180235.245；DOI：10.1016/j.ajpath.2011.09.020)
Neovascular retinal disease is a leading cause of blindness orchestrated by inflammatory responses. Although noninfectious uveoretinitis is mediated by CD4(+) T cells, in the persistent phase of disease, angiogenic responses are observed, along with degeneration of the retina. Full clinical manifestation relies on myeloid-derived cells, which are phenotypically distinct from, but potentially sharing common effector responses to age-related macular degeneration. To interrogate inflammation-mediated angiogenesis, we investigated experimental autoimmune uveoretinitis, an animal model for human uveitis. After the initial acute phase of severe inflammation, the retina sustains a persistent low-grade inflammation with tissue-infiltrating leukocytes for over 4 months. During this persistent phase, angiogenesis is observed as retinal neovascular membranes that arise from inflamed venules and postcapillary venules, increase in size as the disease progresses, and are associated with infiltrating arginase-1(+) macrophages. In the absence of thrombospondin-1, retinal neovascular membranes are markedly increased and are associated with arginase-1(-) CD68(+) macrophages, whereas deletion of the chemokine receptor CCR2 resulted in reduced retinal neovascular membranes in association with a predominant neutrophil infiltrate. CCR2 is important for macrophage recruitment to the retina in experimental autoimmune uveoretinitis and promotes chronicity in the form of a persistent angiogenesis response, which in turn is regulated by constitutive expression of angiogenic inhibitors like thrombospondin-1. This model offers a new platform to dissect the molecular and cellular pathology of inflammation-induced ocular angiogenesis. (Am J. Pathol 2012, 180:235-245; DOI: 10.1016/j.ajpath.2011.09.020)