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- Title
Identifying Hyperreflective Foci in Diabetic Retinopathy via VEGF-Induced Local Self-Renewal of CX3CR1+ Vitreous Resident Macrophages.
- Authors
Yamaguchi, Muneo; Nakao, Shintaro; Wada, Iori; Matoba, Tetsuya; Arima, Mitsuru; Kaizu, Yoshihiro; Shirane, Mariko; Ishikawa, Keijiro; Nakama, Takahito; Murakami, Yusuke; Mizuochi, Masaharu; Shiraishi, Wataru; Yamasaki, Ryo; Hisatomi, Toshio; Ishibashi, Tatsuro; Shibuya, Masabumi; Stitt, Alan W.; Sonoda, Koh-Hei
- Abstract
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-vascular endothelial growth factor (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+ 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.
- Subjects
VASCULAR endothelial growth factors; MACROPHAGES; RESEARCH funding; DIABETIC retinopathy; RETINAL degeneration; ANIMALS; OPTICAL coherence tomography; MICE; LONGITUDINAL method; DIABETES
- Publication
Diabetes, 2022, Vol 71, Issue 12, p2685
- ISSN
0012-1797
- Publication type
Article
- DOI
10.2337/db21-0247