Retinal microglia are critical for subretinal neovascular formation

Usui‐Ouchi, Ayumi; Usui, Yoshihiko; Kurihara, Toshihide; Aguilar, Edith; Dorrell, Michael I.; Ideguchi, Yoichiro; Sakimoto, Susumu; Bravo, Stephen; Friedlander, Martin

doi:10.1172/jci.insight.137317

Cited by 27 publications

(21 citation statements)

References 52 publications

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“…Overexpression of VEGF contributes to retinal neoangiogenesis, whereas the translocation of HIF-1 activates transcription of genes involved in angiogenesis. Additionally, microglia activation and secretion of CCL2, have been implicated in the formation of subretinal neovascular tufts in the retina of Vldlr –/– mice ( 70 ). Considering the proliferative stage of DR, recent studies have shown that microglia are hyperglycolytic during pathological angiogenesis in the OIR model ( 71 ).…”

Section: Mediators Of Inflammation In Diabetic Retinopathymentioning

confidence: 99%

Microglia and Inflammatory Responses in Diabetic Retinopathy

2020

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Diabetic retinopathy is a vision-threatening disease affecting neurons and microvasculature of the retina. The development of this disease is associated with the action of inflammatory factors that are connected to the activation of microglial cells, the resident tissue macrophages of the CNS. In the quiescent state, microglial cells help maintain tissue homeostasis in the retina through phagocytosis and control of low-grade inflammation. However, prolonged tissue stress due to hyperglycemia primes microglia to become overly reactive with the concomitant production of pro-inflammatory cytokines and chemokines causing chronic inflammation. In this review, we provide evidence of microglial cell activation and pro-inflammatory molecules associated with the development and progression of diabetic retinopathy. We further highlight innovative animal models that can mimic the disease in humans and discuss strategies in modulating microglial-mediated inflammation as potential therapeutic approaches in managing the disease.

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Section: Mediators Of Inflammation In Diabetic Retinopathymentioning

confidence: 99%

Microglia and Inflammatory Responses in Diabetic Retinopathy

2020

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“…In Vldlr –/– mice, mistargeted neurites of horizontal cells act as a scaffold for growing neovascularization ( Johnson et al, 2015 ). VEGFA produced by RPE cells in Vldlr –/– mice can induce subretinal infiltration of microglia/macrophages, which can migrate into the ONL and promote the formation of subretinal NV ( Usui-Ouchi et al, 2020 ). Thus, overexpression of VEGFA in photoreceptors and RPE cells, mistargeted neurites of horizontal cells, and activated microglial cells are the three major mechanisms of retinal neovascularization in Vldlr –/– mice, which represent the function of Vldlr in lipid metabolism and reelin signaling, respectively.…”

Section: Animal Models Of Type 3 Macular Neovascularizationmentioning

confidence: 99%

Clinical Pathological Features and Current Animal Models of Type 3 Macular Neovascularization

Wei

Chen

et al. 2021

Front. Neurosci.

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Type 3 macular neovascularization (MNV3), or retinal angiomatous proliferation (RAP), is a distinct type of neovascular age-related macular degeneration (AMD), which is a leading cause of vision loss in older persons. During the past decade, systematic investigation into the clinical, multimodal imaging, and histopathological features and therapeutic outcomes has provided important new insight into this disease. These studies favor the retinal origin of MNV3 and suggest the involvement of retinal hypoxia, inflammation, von Hippel–Lindau (VHL)–hypoxia-inducible factor (HIF)–vascular endothelial growth factor (VEGF) pathway, and multiple cell types in the development and progression of MNV3. Several mouse models, including the recently built Rb/p107/Vhl triple knockout mouse model by our group, have induced many of the histological features of MNV3 and provided much insight into the underlying pathological mechanisms. These models have revealed the roles of retinal hypoxia, inflammation, lipid metabolism, VHL/HIF pathway, and retinoblastoma tumor suppressor (Rb)–E2F cell cycle pathway in the development of MNV3. This article will summarize the clinical, multimodal imaging, and pathological features of MNV3 and the diversity of animal models that exist for MNV3, as well as their strengths and limitations.

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“…Retinal angiomatous proliferation (RAP), also known as macular neovascularization type 3, is present in up to 15% of patients with newly diagnosed neovascular AMD [ 4 ] and is associated with an accumulation of myeloid cells at the microscopic level, including resident microglia or blood-derived infiltrating macrophages [ 5 , 30 ]. Using MG-specific reporter mice and RNA sequencing of sorted retinal MG, this study revealed that retinal microglia proliferate during RAP formation and represent the dominant myeloid cell population at RAP compared with only a few infiltrating blood-derived macrophages.…”

Section: Discussionmentioning

confidence: 99%

Transcriptional and Distributional Profiling of Microglia in Retinal Angiomatous Proliferation

Schlecht

Wolf

Boneva

et al. 2022

IJMS

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Macular neovascularization type 3, formerly known as retinal angiomatous proliferation (RAP), is a hallmark of age-related macular degeneration and is associated with an accumulation of myeloid cells, such as microglia (MG) and infiltrating blood-derived macrophages (MAC). However, the contribution of MG and MAC to the myeloid cell pool at RAP sites and their exact functions remain unknown. In this study, we combined a microglia-specific reporter mouse line with a mouse model for RAP to identify the contribution of MG and MAC to myeloid cell accumulation at RAP and determined the transcriptional profile of MG using RNA sequencing. We found that MG are the most abundant myeloid cell population around RAP, whereas MAC are rarely, if ever, associated with late stages of RAP. RNA sequencing of RAP-associated MG showed that differentially expressed genes mainly contribute to immune-associated processes, including chemotaxis and migration in early RAP and proliferative capacity in late RAP, which was confirmed by immunohistochemistry. Interestingly, MG upregulated only a few angiomodulatory factors, suggesting a rather low angiogenic potential. In summary, we showed that MG are the dominant myeloid cell population at RAP sites. Moreover, MG significantly altered their transcriptional profile during RAP formation, activating immune-associated processes and exhibiting enhanced proliferation, however, without showing substantial upregulation of angiomodulatory factors.

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Retinal microglia are critical for subretinal neovascular formation

Cited by 27 publications

References 52 publications

Microglia and Inflammatory Responses in Diabetic Retinopathy

Microglia and Inflammatory Responses in Diabetic Retinopathy

Clinical Pathological Features and Current Animal Models of Type 3 Macular Neovascularization

Transcriptional and Distributional Profiling of Microglia in Retinal Angiomatous Proliferation

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