June 2023
Volume 64, Issue 8
Open Access
ARVO Annual Meeting Abstract  |   June 2023
Inhibition of myeloid Pfkfb3-mediated glycolysis decreases subretinal fibrosis of mouse nAMD
Author Affiliations & Notes
  • Yongfeng Cai
    Vascular Biology Center, Augusta University, Augusta, Georgia, United States
  • Qiuhua Yang
    Vascular Biology Center, Augusta University, Augusta, Georgia, United States
  • Qian Ma
    Vascular Biology Center, Augusta University, Augusta, Georgia, United States
  • Ruth B Caldwell
    Vascular Biology Center, Augusta University, Augusta, Georgia, United States
  • Akrit Sodhi
    Johns Hopkins Medicine, Baltimore, Maryland, United States
  • Yuqing Huo
    Vascular Biology Center, Augusta University, Augusta, Georgia, United States
  • Footnotes
    Commercial Relationships   Yongfeng Cai None; Qiuhua Yang None; Qian Ma None; Ruth Caldwell None; Akrit Sodhi None; Yuqing Huo None
  • Footnotes
    Support  None
Investigative Ophthalmology & Visual Science June 2023, Vol.64, 3240. doi:
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    • Get Citation

      Yongfeng Cai, Qiuhua Yang, Qian Ma, Ruth B Caldwell, Akrit Sodhi, Yuqing Huo; Inhibition of myeloid Pfkfb3-mediated glycolysis decreases subretinal fibrosis of mouse nAMD. Invest. Ophthalmol. Vis. Sci. 2023;64(8):3240.

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      © ARVO (1962-2015); The Authors (2016-present)

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Abstract

Purpose : Subretinal fibrosis has been seen as one of major reasons why neovascular age-related macular degeneration (nAMD) does not respond to anti-VEGF treatment. Macrophages are critically involved in the development of pathological fibrosis. 6-phosphofructo-2-kinase/fructose-2, 6-bisphosphatase isoform 3 (PFKFB3)-mediated glycolysis is critical for macrophage activation. However, the effect of myeloid Pfkfb3-associated glycolysis in the subretinal fibrosis niche is still unknown. In this study, we investigated whether knockout of myeloid Pfkfb3 suppresses subretinal fibrosis in mouse nAMD models.

Methods : Laser-induced or spontaneous CNV in C57BL/6j mice or very low-density lipoprotein receptor-deficient (Vldlr-/-) mice were used as mouse nAMD models. Pfkfb3 expression was examined in murine subretinal fibrotic lesions. The fibrotic lesions and infiltrating macrophages in retinal pigment epithelial (RPE)-choroidal complex were analyzed by immunostaining of collagen I, ACTA2 and F4/80 in Pfkfb3 heterozygous (Pfkfb3+/-) mice and myeloid Pfkfb3 deficient (Pfkfb3ΔMΦ) mice in both models. In an in vitro assay, bone marrow-derived macrophages (BMDMs) from Pfkfb3ΔMΦ mice and Pfkfb3WT mice were treated with transforming growth factor beta-2 (TGFβ-2) to induce macrophage to myofibroblast transition (MMT). RPE cells were treated with TGFβ-2 to differentiate to epithelial-to-mesenchymal transition (EMT) cells. Epithelial cell markers and myofibroblast markers were analyzed by qPCR and Western blot.

Results : Pfkfb3 expression in macrophages infiltrating in the subretinal fibrotic lesions were increased. The development of subretinal fibrosis was suppressed in Pfkfb3+/- and Pfkfb3ΔMΦ mice of both models. In vitro assay TGFβ-2 induced-MMT was suppressed for Pfkfb3ΔMΦ BMDMs and EMT induction was decreased when RPE cells were cultured with the medium of Pfkfb3ΔMΦ BMDMs.

Conclusions : Inhibition of myeloid Pfkfb3-mediated glycolysis prevents EMT and MMT induction and the development of subretinal fibrosis in nAMD mouse models. Myeloid Pfkfb3 is a promising therapeutic target in nAMD.

This abstract was presented at the 2023 ARVO Annual Meeting, held in New Orleans, LA, April 23-27, 2023.

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