Suppression of myeloid PFKFB3-driven glycolysis protects mice from choroidal neovascularization.

Abstract

BACKGROUND AND PURPOSE:

Pathological angiogenesis is a major cause of irreversible blindness in individuals with neovascular age-related macular degeneration (nAMD). Macrophages and microglia (MΦ) contribute to aberrant ocular angiogenesis. However, the role of glucose metabolism of MΦ in nAMD is still undefined. Here, we have investigated the involvement of glycolysis, driven by the kinase/phosphatase PFKFB3, in the development of choroidal neovascularization (CNV).

EXPERIMENTAL APPROACH:

CNV was induced in mice with laser photocoagulation. Choroid/retinal pigment epithelium (RPE) complexes and MΦ were isolated for analysis by qRT-PCR, western blot, flow cytometry, immunostaining, metabolic measurements and angiogenesis assays.

KEY RESULTS:

MΦ accumulated within the CNV of murine nAMD models and expressed high levels of glycolysis-related enzymes and M1/M2 polarization markers. This phenotype of hyper-glycolytic and activated MΦ was replicated in bone marrow-derived macrophages stimulated by necrotic RPE in vitro. Myeloid cell-specific knockout of PFKFB3, a key glycolytic activator, attenuated pathological neovascularization in laser-induced CNV, which was associated with decreased expression of MΦ polarization markers and pro-angiogenic factors, along with decreased sprouting of vessels in choroid/RPE complexes. Mechanistically, necrotic RPE increased PFKFB3-driven glycolysis in macrophages, leading to activation of HIF-1α/HIF-2α and NF-κB, and subsequent induction of M1/M2 markers and pro-angiogenic cytokines, finally promoting macrophage reprogramming towards an angiogenic phenotype to facilitate development of CNV. The PFKFB3 inhibitor AZ67 also inhibited activation of HIF-1α/HIF-2α and NF-κB signalling and almost completely prevented laser-induced CNV in mice.

CONCLUSIONS AND IMPLICATIONS:

Modulation of PFKFB3-mediated macrophage glycolysis and activation is a promising strategy for the treatment of nAMD.

• Authors: Zhiping Liu, Xiaoxiao Mao, Qiuhua Yang, Xiaoyu Zhang, Jiean Xu, Qian Ma, Yaqi Zhou, Qingen Da, Yongfeng Cai, Anu Sopeyin, Zheng Dong, Mei Hong, Ruth B Caldwell, Akrit Sodhi, Yuqing Huo
• Journal: British journal of pharmacology (Br J Pharmacol) Vol. 179 Issue 22 Pg. 5109-5131 (11 2022) ISSN: 1476-5381 [Electronic] England
• PMID: 35830274 (Publication Type: Journal Article)
• Copyright: © 2022 The Authors. British Journal of Pharmacology published by John Wiley & Sons Ltd on behalf of British Pharmacological Society.

Chemical References

• Basic Helix-Loop-Helix Transcription Factors
• Cytokines
• NF-kappa B
• PFKFB3 protein, mouse
• Phosphofructokinase-2
• Phosphoric Monoester Hydrolases
• Glucose

Topics

• Animals
• Basic Helix-Loop-Helix Transcription Factors (metabolism)
• Choroidal Neovascularization (etiology, metabolism, prevention & control)
• Cytokines (metabolism)
• Disease Models, Animal
• Glucose
• Glycolysis
• Mice
• Mice, Inbred C57BL
• NF-kappa B (metabolism)
• Phosphofructokinase-2
• Phosphoric Monoester Hydrolases