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

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

研究成果: ジャーナルへの寄稿学術誌査読

6 被引用数 (Scopus)

抄録

Intraretinal hyperreflective foci (HRF) are significant biomarkers for diabetic macular edema. However, HRF at the vitreoretinal interface (VRI) have not been exam-ined 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+/2) mice, indicat-ing macrophage activation was modulated by elevated VEGF rather than the diabetic milieu. Macrophage depletion significantly reduced HRF at the VRI (P < 0.01). Fur-thermore, BrdU administration in Ccr2rfp/+Cx3cr1gfp/+ vegfa+/2 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 to-gether, 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.

本文言語英語
ページ(範囲)2685-2701
ページ数17
ジャーナルDiabetes
71
12
DOI
出版ステータス出版済み - 12月 2022

!!!All Science Journal Classification (ASJC) codes

  • 内科学
  • 内分泌学、糖尿病および代謝内科学

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