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

Publisher: American Association for the Advancement of Science Country of Publication: United States NLM ID: 101505086 Publication Model: Print Cited Medium: Internet ISSN: 1946-6242 (Electronic) Linking ISSN: 19466234 NLM ISO Abbreviation: Sci Transl Med Subsets: MEDLINE

Original Publication: Washington, DC : American Association for the Advancement of Science

Endothelial Cells*/metabolism ; Glycolysis*; Animals ; Macrophages/metabolism ; Mice ; Mice, Knockout ; Phosphofructokinase-2/metabolism

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.
(Copyright © 2020 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.)

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R01 EY030500 United States EY NEI NIH HHS; R01 HL126949 United States HL NHLBI NIH HHS; R01 EY029238 United States EY NEI NIH HHS; R01 EY017017 United States EY NEI NIH HHS; R01 HL142097 United States HL NHLBI NIH HHS; R01 HL134934 United States HL NHLBI NIH HHS; I01 BX003221 United States BX BLRD VA; R01 EY011766 United States EY NEI NIH HHS; U54 HD090255 United States HD NICHD NIH HHS; R01 EY030904 United States EY NEI NIH HHS; R01 EY029750 United States EY NEI NIH HHS; R01 HL147159 United States HL NHLBI NIH HHS; R01 EY030140 United States EY NEI NIH HHS; IK6 BX005228 United States BX BLRD VA; R01 EY029751 United States EY NEI NIH HHS

EC 2.7.1.105 (Phosphofructokinase-2)

Date Created: 20200808 Date Completed: 20210623 Latest Revision: 20211114

20231215

PMC7751280

10.1126/scitranslmed.aay1371

32759274