Local partial depletion of <scp>CD</scp>11b<sup>+</sup> cells and their influence on choroidal neovascularization using the <scp>CD</scp>11b‐<scp>HSVTK</scp> mouse model

Brockmann, Claudia; Kociok, Norbert; Dege, Sabrina; Davids, Anja‐Maria; Brockmann, Tobias; Miller, Kelly R.; Joussen, Antonia M.

doi:10.1111/aos.13716

Cited by 5 publications

(3 citation statements)

References 45 publications

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“…Microglia are known to increase VEGF expression after laser injury [39], potentially implicating microglia as pro-angiogenic. Alternatively, depletion of CD11b + cells in the retina prior to laser injury, which depletes retinal microglia in addition to other cell types, has no effect upon CNV area [40], suggesting that microglia are not necessary for CNV compared to monocyte-derived macrophages. Because most prior studies do not sufficiently discriminate between microglia and infiltrating macrophages using multi-parameter flow cytometry or advanced fate mapping methods, the role of microglia during CNV remains unclear and more advanced methodologies will be needed to determine their function.…”

Section: Discussionmentioning

confidence: 99%

Ocular macrophage origin and heterogeneity during steady state and experimental choroidal neovascularization

Droho

Thomson

Makinde

et al. 2020

J Neuroinflammation

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Background Neovascular age-related macular degeneration (nAMD) commonly causes vision loss from aberrant angiogenesis, termed choroidal neovascularization (CNV). Macrophages are heterogeneous cells that are necessary for experimental CNV, present in human CNV samples, and can display diverse functions, which are dependent upon both their origin and tissue microenvironment. Despite these associations, choroidal macrophage heterogeneity remains unexplored. Methods We performed multi-parameter flow cytometry on wildtype (WT) and Ccr2−/− mice after laser injury to identify macrophage subtypes, and determine which subsets originate from classical monocytes. To fate map tissue resident macrophages at steady state and after laser injury, we used the Cx3cr1CreER/+ ; Rosa26zsGFP/+ mouse model. We reanalyzed previously published single-cell RNA-seq of human choroid samples from healthy and nAMD patients to investigate human macrophage heterogeneity, disease association, and function. Results We identified 4 macrophage subsets in mice: microglia, MHCII+CD11c−, MHCII+CD11c+, and MHCII−. Microglia are tissue resident macrophages at steady state and unaffected by laser injury. At steady state, MHCII− macrophages are long lived, tissue resident macrophages, while MHCII+CD11c− and MHCII+CD11c+ macrophages are partially replenished from blood monocytes. After laser injury, MHCII+CD11c− macrophages are entirely derived from classical monocytes, MHCII− macrophages originate from classical monocytes (90%) and an expansion of tissue resident macrophages (10%), and MHCII+CD11c+ macrophages are derived from classical monocytes (70%), non-classical monocytes (10%), and an expansion of tissue resident macrophages (20%). Single-cell RNA-seq analysis of human choroid found 5 macrophage subsets: two MHCII+CD11C− and three MHCII+CD11C+ populations. One MHCII+CD11C+ subset was 78% derived from a patient with nAMD. Differential expression analysis identified up-regulation of pro-angiogenic gene expression in one MHCII+CD11C− and two MHCII+CD11C+ subsets, including the disease-associated cluster. The upregulated MHCII+CD11C− pro-angiogenic genes were unique compared to the increased MHCII+CD11C+ angiogenesis genes. Conclusions Macrophage origin impacts heterogeneity at steady state and after laser injury in mice. Both mice and human patients demonstrate similar macrophage subtypes. Two discrete pro-angiogenic macrophage populations exist in the human choroid. Targeting specific, pro-angiogenic macrophage subsets is a potential novel therapeutic for nAMD.

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Section: Discussionmentioning

confidence: 99%

Ocular macrophage origin and heterogeneity during steady state and experimental choroidal neovascularization

Droho

Thomson

Makinde

et al. 2020

J Neuroinflammation

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“…We wondered whether the proangiogenic activity of CD11b + immune cells was based on the local resident CD11b + macrophages and microglia, on the CD11b + circulating monocytes, or both. This aspect was clarified in a recent study by Brockmann et al, who found that inhibition of the local resident CD11b + macrophages and microglia did not provide any significant reduction of CNV size and concluded that the CNV-related activity of CD11b + cells may come from the systemic circulation. This concluding hypothesis by Brockmann et al aligns with the findings of our study.…”

Section: Discussionmentioning

confidence: 98%

“…This aspect was clarified in a recent study by Brockmann et al, who found that inhibition of the local resident CD11b + macrophages and microglia did not provide any significant reduction of CNV size and concluded that the CNV-related activity of CD11b + cells may come from the systemic circulation. This concluding hypothesis by Brockmann et al aligns with the findings of our study.…”

Section: Discussionmentioning

confidence: 98%

Association of CD11b⁺Monocytes and Anti–Vascular Endothelial Growth Factor Injections in Treatment of Neovascular Age-Related Macular Degeneration and Polypoidal Choroidal Vasculopathy

et al. 2019

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IMPORTANCE CD11b + immune cells have been implicated in the formation of choroidal neovascularization in experimental studies on animals and disease-association studies on humans. However, the clinical importance of such observations remains unknown. OBJECTIVE To investigate whether the proportion of CD11b + circulating monocytes is associated with the number of anti-vascular endothelial growth factor (anti-VEGF) injections in neovascular age-related macular degeneration (AMD) and polypoidal choroidal vasculopathy (PCV).

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Systemic Rho-kinase inhibition using fasudil in mice with oxygen-induced retinopathy

Brockmann

Corkhill

Jaroslawska

et al. 2019

Graefes Arch Clin Exp Ophthalmol

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Local partial depletion of CD11b⁺ cells and their influence on choroidal neovascularization using the CD11b‐HSVTK mouse model

Cited by 5 publications

References 45 publications

Ocular macrophage origin and heterogeneity during steady state and experimental choroidal neovascularization

Ocular macrophage origin and heterogeneity during steady state and experimental choroidal neovascularization

Association of CD11b⁺Monocytes and Anti–Vascular Endothelial Growth Factor Injections in Treatment of Neovascular Age-Related Macular Degeneration and Polypoidal Choroidal Vasculopathy

Systemic Rho-kinase inhibition using fasudil in mice with oxygen-induced retinopathy

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Local partial depletion of CD11b+ cells and their influence on choroidal neovascularization using the CD11b‐HSVTK mouse model

Cited by 5 publications

References 45 publications

Ocular macrophage origin and heterogeneity during steady state and experimental choroidal neovascularization

Ocular macrophage origin and heterogeneity during steady state and experimental choroidal neovascularization

Association of CD11b+Monocytes and Anti–Vascular Endothelial Growth Factor Injections in Treatment of Neovascular Age-Related Macular Degeneration and Polypoidal Choroidal Vasculopathy

Systemic Rho-kinase inhibition using fasudil in mice with oxygen-induced retinopathy

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Product

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Local partial depletion of CD11b⁺ cells and their influence on choroidal neovascularization using the CD11b‐HSVTK mouse model

Association of CD11b⁺Monocytes and Anti–Vascular Endothelial Growth Factor Injections in Treatment of Neovascular Age-Related Macular Degeneration and Polypoidal Choroidal Vasculopathy