Glycolysis links reciprocal activation of myeloid cells and endothelial cells in the retinal angiogenic niche.
Glycolysis links reciprocal activation of myeloid cells and endothelial cells in the retinal angiogenic niche.
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糖酵解将视网膜血管生成微环境中骨髓细胞和内皮细胞的相互激活联系起来
DOI：
10.1126/scitranslmed.aay1371
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发表时间：
2020-08-05
影响因子：
17.1
通讯作者：
Huo Y
中科院分区：
文献类型：
--
作者：
Liu Z;Xu J;Ma Q;Zhang X;Yang Q;Wang L;Cao Y;Xu Z;Tawfik A;Sun Y;Weintraub NL;Fulton DJ;Hong M;Dong Z;Smith LEH;Caldwell RB;Sodhi A;Huo Y
在病理性视网膜血管生成中，糖酵解增加促进髓样细胞和内皮细胞之间的相互激活。眼血管生成是视力障碍和失明的主要原因。小胶质细胞/巨噬细胞已被证明有助于病理性血管生成;然而，它们的表型和在视网膜血管生成中的作用尚未完全阐明。现在，Liu等人表明，在病理性视网膜血管生成中，小胶质细胞/巨噬细胞高度糖酵解并获得病理性表型，其特征在于促炎和促血管生成细胞因子的高表达。他们称这些细胞为病理性视网膜血管生成相关糖酵解巨噬细胞/小胶质细胞（PRAGM）。糖酵解激活触发PRAGM，这表明靶向代谢变化的策略可以有效治疗病理性视网膜血管生成。病理性视网膜血管生成中不同细胞成分之间代谢信号的协调知之甚少。在这里，我们发现，在病理性血管生成血管龛，视网膜髓样细胞，特别是巨噬细胞/小胶质细胞，是空间上相邻的内皮细胞（EC），是高度糖酵解。我们将这些巨噬细胞/小胶质细胞称为病理性视网膜血管生成相关糖酵解巨噬细胞/小胶质细胞（PRAGM），它们表现出独特的血管生成表型，M1和M2标志物的表达增加，促炎细胞因子和促血管生成细胞因子的产生增加。PRAGM的表型在由缺氧视网膜EC产生的乳酸刺激的骨髓源性巨噬细胞或视网膜小胶质细胞中重现。敲除髓系细胞中的糖酵解激活剂6-磷酸果糖-2-激酶/果糖-2，6-二磷酸酶（PFKFB 3;啮齿动物为Pfkfb 3），损害巨噬细胞/小胶质细胞获得血管生成表型的能力，使其无法促进氧诱导增殖性视网膜病变小鼠模型中的EC增殖和发芽以及病理性新血管形成。在机制上，过度糖酵解的巨噬细胞/小胶质细胞产生大量乙酰辅酶A，导致组蛋白乙酰化和PRAGM相关基因诱导，从而将巨噬细胞/小胶质细胞重编程为血管生成表型。这些发现揭示了糖酵解代谢物作为视网膜血管生成龛中巨噬细胞/小胶质细胞和EC相互激活的引发剂的关键作用，并表明靶向这些细胞类型之间的代谢通讯的策略可能在治疗病理性视网膜血管生成中有效。
Increased glycolysis facilitates reciprocal activation between myeloid cells and endothelial cells in pathological retinal angiogenesis. PRAGMatic myeloid cells Ocular angiogenesis is a major cause of vision impairments and blindness. Microglia/macrophages have been shown to contribute to pathological angiogenesis; however, their phenotype and role in retinal angiogenesis has not been completely elucidated. Now, Liu et al. show that in pathological retinal angiogenesis, microglia/macrophages are highly glycolytic and acquire a pathological phenotype, characterized by high expression of proinflammatory and proangiogenic cytokines. They called these cells pathological retinal angiogenesis–associated glycolytic macrophages/microglia (PRAGMs). Glycolytic activation triggered PRAGMs, suggesting that strategies targeting metabolic changes could be effective in treating pathological retinal angiogenesis. The coordination of metabolic signals among different cellular components in pathological retinal angiogenesis is poorly understood. Here, we showed that in the pathological angiogenic vascular niche, retinal myeloid cells, particularly macrophages/microglia that are spatially adjacent to endothelial cells (ECs), are highly glycolytic. We refer to these macrophages/microglia that exhibit a unique angiogenic phenotype with increased expression of both M1 and M2 markers and enhanced production of both proinflammatory and proangiogenic cytokines as pathological retinal angiogenesis–associated glycolytic macrophages/microglia (PRAGMs). The phenotype of PRAGMs was recapitulated in bone marrow–derived macrophages or retinal microglia stimulated by lactate that was produced by hypoxic retinal ECs. Knockout of 6-phosphofructo-2-kinase/fructose-2, 6-bisphosphatase (PFKFB3; Pfkfb3 for rodents), a glycolytic activator in myeloid cells, impaired the ability of macrophages/microglia to acquire an angiogenic phenotype, rendering them unable to promote EC proliferation and sprouting and pathological neovascularization in a mouse model of oxygen-induced proliferative retinopathy. Mechanistically, hyperglycolytic macrophages/microglia produced large amount of acetyl–coenzyme A, leading to histone acetylation and PRAGM-related gene induction, thus reprogramming macrophages/microglia into an angiogenic phenotype. These findings reveal a critical role of glycolytic metabolites as initiators of reciprocal activation of macrophages/microglia and ECs in the retinal angiogenic niche and suggest that strategies targeting the metabolic communication between these cell types may be efficacious in the treatment of pathological retinal angiogenesis.
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内皮腺苷 A2a 受体介导的糖酵解对于病理性视网膜血管生成至关重要
影响因子：
16.6
作者：
Liu Z;Yan S;Wang J;Xu Y;Wang Y;Zhang S;Xu X;Yang Q;Zeng X;Zhou Y;Gu X;Lu S;Fu Z;Fulton DJ;Weintraub NL;Caldwell RB;Zhang W;Wu C;Liu XL;Chen JF;Ahmad A;Kaddour-Djebbar I;Al-Shabrawey M;Li Q;Jiang X;Sun Y;Sodhi A;Smith L;Hong M;Huo Y
通讯作者：
Huo Y
影响因子：
9.3
作者：
Kohno H;Koso H;Okano K;Sundermeier TR;Saito S;Watanabe S;Tsuneoka H;Sakai T
通讯作者：
Sakai T
影响因子：
44.1
作者：
通讯作者：
--
影响因子：
4.4
作者：
Kataoka, Keiko;Nishiguchi, Koji M.;Terasaki, Hiroko
通讯作者：
Terasaki, Hiroko
影响因子：
20.3
作者：
Fantin, Alessandro;Vieira, Joaquim M.;Ruhrberg, Christiana
通讯作者：
Ruhrberg, Christiana