Glycolysis links reciprocal activation of myeloid cells and endothelial cells in the retinal angiogenic niche

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Science Translational Medicine  05 Aug 2020:
Vol. 12, Issue 555, eaay1371
DOI: 10.1126/scitranslmed.aay1371

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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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