Proangiogenic characteristics of activated macrophages from patients with age-related macular degeneration

Hagbi-Levi, Shira; Grunin, Michelle; Jaouni, Tareq; Tiosano, Liran; Rinsky, Batya; Elbaz-Hayoun, Sarah; Peled, Amnon; Chowers, Itay

doi:10.1016/j.neurobiolaging.2016.11.018

Cited by 32 publications

(47 citation statements)

References 88 publications

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“…Overall, our findings are timely, given a recent report that showed that there is an increase in the number of choroidal macrophages in human eyes with AMD (36), strongly implicating a pathogenic role for macrophages in disease. Moreover, our findings may partially explain why activated macrophages derived from neovascular AMD patients have proangiogenic characteristics (37,38). While other groups have suggested that endothelial miR-150 may suppress pathologic ocular neovascularization (39,40), our findings highlight a distinct, macrophage-specific role for miR-150 that, in fact, promotes pathological ocular neovascularization.…”

Section: Discussionsupporting

confidence: 46%

Macrophage microRNA-150 promotes pathological angiogenesis as seen in age-related macular degeneration

Lin¹,

Moolani²,

Sène³

et al. 2018

JCI Insight

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Macrophage aging is pathogenic in diseases of the elderly, including age-related macular degeneration (AMD), a leading cause of blindness in older adults. However, the role of microRNAs, which modulate immune processes, in regulating macrophage dysfunction and thereby promoting age-associated diseases is underexplored. Here, we report that microRNA-150 (miR-150) coordinates transcriptomic changes in aged murine macrophages, especially those associated with aberrant lipid trafficking and metabolism in AMD pathogenesis. Molecular profiling confirmed that aged murine macrophages exhibit dysregulated ceramide and phospholipid profiles compared with young macrophages. Of translational relevance, upregulation of miR-150 in human peripheral blood mononuclear cells was also significantly associated with increased odds of AMD, even after controlling for age. Mechanistically, miR-150 directly targets stearoyl-CoA desaturase-2, which coordinates macrophage-mediated inflammation and pathologic angiogenesis, as seen in AMD, in a VEGF-independent manner. Together, our results implicate miR-150 as pathogenic in AMD and provide potentially novel molecular insights into diseases of aging.

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Section: Discussionsupporting

confidence: 46%

Macrophage microRNA-150 promotes pathological angiogenesis as seen in age-related macular degeneration

Lin¹,

Moolani²,

Sène³

et al. 2018

JCI Insight

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“…Although the directionality of these changes did not correspond perfectly between mice and humans, our data suggest that broad dysregulation of cholesterol homeostasis in both aging and disease is associated with altered oxysterol signatures. These findings build on recent reports that monocytes isolated from patients with neovascular AMD do indeed exhibit an altered immune-related transcriptomic signature [ 44 ] and that these cells, when activated into macrophages, demonstrate proangiogenic characteristics that may contribute to disease pathogenesis [ 45 ]. Past studies have also shown that in the outer retina, accumulation of cholesterol oxidation products such as 7-KC can disrupt the immune environment and transform resident macrophages into disease-promoting cells [ 46 ].…”

Section: Discussionsupporting

confidence: 81%

Oxysterol Signatures Distinguish Age-Related Macular Degeneration from Physiologic Aging

et al. 2018

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Macrophage aging is pathogenic in numerous diseases, including age-related macular degeneration (AMD), a leading cause of blindness in older adults. Although prior studies have explored the functional consequences of macrophage aging, less is known about its cellular basis or what defines the transition from physiologic aging to disease. Here, we show that despite their frequent self-renewal, macrophages from old mice exhibited numerous signs of aging, such as impaired oxidative respiration. Transcriptomic profiling of aged murine macrophages revealed dysregulation of diverse cellular pathways, especially in cholesterol homeostasis, that manifested in altered oxysterol signatures. Although the levels of numerous oxysterols in human peripheral blood mononuclear cells and plasma exhibited age-associated changes, plasma 24-hydroxycholesterol levels were specifically associated with AMD. These novel findings demonstrate that oxysterol levels can discriminate disease from physiologic aging. Furthermore, modulation of cholesterol homeostasis may be a novel strategy for treating age-associated diseases in which macrophage aging is pathogenic.

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“…Thus, delivery of exogenous AIBP/apoA-I is a promising treatment that could reduce CNV or overcome anti-VEGF resistance for patients with neovascular AMD. Substantial evidence indicate that macrophages have an important role in the pathogenesis of wet AMD in both animal models and human patients [8][9][10][27][28][29][30][31][32][33] . Oxidized low-density lipoprotein and macrophages have been detected in CNV membranes from eyes with AMD 34 .…”

Section: Discussionmentioning

confidence: 99%

Combination of apolipoprotein-A-I/apolipoprotein-A-I binding protein and anti-VEGF treatment overcomes anti-VEGF resistance in choroidal neovascularization in mice

et al. 2020

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Many patients of choroidal neovascularization (CNV) are unresponsive to the current anti-VEGF treatment. The mechanisms for anti-VEGF resistance are poorly understood. We explore the unique property of the apolipoprotein A-I (apoA-I) binding protein (AIBP) that enhances cholesterol efflux from endothelial cells and macrophages to thereby limit angiogenesis and inflammation to tackle anti-VEGF resistance in CNV. We show that laser-induced CNV in mice with increased age showed increased resistance to anti-VEGF treatment, which correlates with increased lipid accumulation in macrophages. The combination of AIBP/ apoA-I and anti-VEGF treatment overcomes anti-VEGF resistance and effectively suppresses CNV. Furthermore, macrophage depletion in old mice restores CNV sensitivity to anti-VEGF treatment and blunts the synergistic effect of combination therapy. These results suggest that cholesterol-laden macrophages play a critical role in inducing anti-VEGF resistance in CNV. Combination therapy by neutralizing VEGF and enhancing cholesterol removal from macrophages is a promising strategy to combat anti-VEGF resistance in CNV.

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Proangiogenic characteristics of activated macrophages from patients with age-related macular degeneration

Cited by 32 publications

References 88 publications

Macrophage microRNA-150 promotes pathological angiogenesis as seen in age-related macular degeneration

Macrophage microRNA-150 promotes pathological angiogenesis as seen in age-related macular degeneration

Oxysterol Signatures Distinguish Age-Related Macular Degeneration from Physiologic Aging

Combination of apolipoprotein-A-I/apolipoprotein-A-I binding protein and anti-VEGF treatment overcomes anti-VEGF resistance in choroidal neovascularization in mice

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