Yamaguchi, Muneo; Nakao, Shintaro; Arima, Mitsuru; Little, Karis; Singh, Aditi; Wada, Iori; Kaizu, Yoshihiro; Zandi, Souska; Garweg, Justus G; Matoba, Tetsuya; Shiraishi, Wataru; Yamasaki, Ryo; Shibata, Kensuke; Go, Yasuhiro; Ishibashi, Tatsuro; Uemura, Akiyoshi; Stitt, Alan W; Sonoda, Koh-Hei (2024). Heterotypic macrophages/microglia differentially contribute to retinal ischaemia and neovascularisation. (In Press). Diabetologia Springer 10.1007/s00125-024-06215-3
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AIMS/HYPOTHESIS
Diabetic retinopathy is characterised by neuroinflammation that drives neuronal and vascular degenerative pathology, which in many individuals can lead to retinal ischaemia and neovascularisation. Infiltrating macrophages and activated retina-resident microglia have been implicated in the progression of diabetic retinopathy, although the distinct roles of these immune cells remain ill-defined. Our aim was to clarify the distinct roles of macrophages/microglia in the pathogenesis of proliferative ischaemic retinopathies.
METHODS
Murine oxygen-induced retinopathy is commonly used as a model of ischaemia-induced proliferative diabetic retinopathy (PDR). We evaluated the phenotype macrophages/microglia by immunostaining, quantitative real-time RT-PCR (qRT-PCR), flow cytometry and scRNA-seq analysis. In clinical imaging studies of diabetic retinopathy, we used optical coherence tomography (OCT) and OCT angiography.
RESULTS
Immunostaining, qRT-PCR and flow cytometry showed expression levels of M1-like macrophages/microglia markers (CD80, CD68 and nitric oxide synthase 2) and M2-like macrophages/microglia markers (CD206, CD163 and macrophage scavenger receptor 1) were upregulated in areas of retinal ischaemia and around neo-vessels, respectively. scRNA-seq analysis of the ischaemic retina revealed distinct ischaemia-related clusters of macrophages/microglia that express M1 markers as well as C-C chemokine receptor 2. Inhibition of Rho-kinase (ROCK) suppressed CCL2 expression and reduced CCR2-positive M1-like macrophages/microglia in areas of ischaemia. Furthermore, the area of retinal ischaemia was reduced by suppressing blood macrophage infiltration not only by ROCK inhibitor and monocyte chemoattractant protein-1 antibody but also by GdCl3. Clinical imaging studies of diabetic retinopathy using OCT indicated potential involvement of macrophages/microglia represented by hyperreflective foci in areas of reduced perfusion.
CONCLUSIONS/INTERPRETATION
These results collectively indicated that heterotypic macrophages/microglia differentially contribute to retinal ischaemia and neovascularisation in retinal vascular diseases including diabetic retinopathy. This adds important new information that could provide a basis for a more targeted, cell-specific therapeutic approach to prevent progression to sight-threatening PDR.
Item Type: |
Journal Article (Original Article) |
|---|---|
Division/Institute: |
04 Faculty of Medicine > Department of Head Organs and Neurology (DKNS) > Clinic of Ophthalmology |
UniBE Contributor: |
Garweg, Justus |
Subjects: |
600 Technology > 610 Medicine & health |
ISSN: |
0012-186X |
Publisher: |
Springer |
Language: |
English |
Submitter: |
Pubmed Import |
Date Deposited: |
09 Jul 2024 12:29 |
Last Modified: |
09 Jul 2024 15:16 |
Publisher DOI: |
10.1007/s00125-024-06215-3 |
PubMed ID: |
38977459 |
Uncontrolled Keywords: |
Diabetic ischaemia Ischaemic retinopathy Macrophage polarisation Microglia Monocyte |
BORIS DOI: |
10.48350/198716 |
URI: |
https://boris.unibe.ch/id/eprint/198716 |
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