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Identifying Hyperreflective Foci in Diabetic Retinopathy via VEGF-induced Local Self-Renewal of CX3CR1+ Vitreous Resident Macrophages

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posted on 2022-10-07, 00:10 authored by Muneo Yamaguchi, Shintaro Nakao, Iori Wada, Tetsuya Matoba, Mitsuru Arima, Yoshihiro Kaizu, Mariko Shirane, Keijiro Ishikawa, Takahito Nakama, Yusuke Murakami, Masaharu Mizuochi, Wataru Shiraishi, Ryo Yamasaki, Toshio Hisatomi, Tatsuro Ishibashi, Masabumi Shibuya, Alan W. Stitt, Koh-Hei Sonoda

Intraretinal hyperreflective foci (HRF) are significant biomarkers for diabetic macular edema. However, HRF at the vitreoretinal interface (VRI) have not been examined in diabetic retinopathy (DR). A prospective observational clinical study with 162 consecutive eyes using OCT imaging showed significantly increased HRF at the VRI during DR progression (P<0.01), which was reversed by anti-VEGF therapy. F4/80+ macrophages increased significantly at the VRI in Kimba (vegfa+/+) or Akimba (Akita × Kimba) mice (both P<0.01), but not in diabetic Akita (Ins2+/-) mice, indicating macrophage activation was modulated by elevated VEGF rather than the diabetic milieu. Macrophage depletion significantly reduced HRF at the VRI (P<0.01). Furthermore, BrdU administration in Ccr2rfp/+Cx3cr1gfp/+ vegfa+/- mice identified a significant contribution of M2-like tissue-resident macrophages (TRMs) at the VRI. Ki-67- and CD11b-positive cells were observed in preretinal tissues of DR patients while exposure of vitreal macrophages to vitreous derived from PDR patients induced a significant proliferation response in vitro (P<0.01). Taken together, the evidence suggests that VEGF drives a local proliferation of vitreous resident macrophages (VRMs) at the VRI during DR. This phenomenon helps to explain the derivation and disease-relevance of the HRF lesions observed through OCT imaging in patients.
 

Funding

This study was supported by grants from JSPS KAKENHI no. 17K11456 (SN), No. 20K09829 (SN), and No.21K16897 (MY), the Charitable Trust Fund for Ophthalmic Research in Commemoration of Santen Pharmaceutical’s Founder (SN), Bayer Retina Award (SN), Novartis Pharma Research Grants (SN), Alcon Pharma Research Grants (SN) Takeda Science Foundation (SN), and The Foundation for The Advancement of Clinical Medicine, Fukuoka, Japan (SN).

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