Glycolysis links reciprocal activation of myeloid cells and endothelial cells in the retinal angiogenic niche
- 5 August 2020
- journal article
- research article
- Published by American Association for the Advancement of Science (AAAS) in Science Translational Medicine
- Vol. 12 (555)
- https://doi.org/10.1126/scitranslmed.aay1371
Abstract
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.Keywords
Funding Information
- National Institutes of Health (R01 EY030500)
- National Institutes of Health (R01 HL134934)
- National Institutes of Health (R01 HL142097)
- National Institutes of Health (R01 EY017017)
- National Institutes of Health (R01 EY030140)
- National Institutes of Health (R01 EY029750)
- National Institutes of Health (EY029238)
- National Institutes of Health (EY030904)
- National Institutes of Health (R01HL147159)
- National Institutes of Health (IK6 RX005228)
- National Institutes of Health (EY011766)
- American Heart Association (19POST34430119)
- National Natural Science Foundation of China (81870324)
- Shenzhen Science and Technology Innovation Committee (JCYJ20170810163238384)
- Shenzhen Science and Technology Innovation Committee (JCYJ20190808155605447)
- Shenzhen Science and Technology Innovation Committee (JCYJ20170412150405310)
- Shenzhen Science and Technology Innovation Committee (2019SHIBS0004)
- Shenzhen Science and Technology Innovation Committee (JCYJ20190808155801648)
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