Macrophage microRNA-150 promotes pathological angiogenesis as seen in age-related macular degeneration
Jonathan B. Lin, Harsh V. Moolani, Abdoulaye Sene, Rohini Sidhu, Pamela Kell, Joseph B. Lin, Zhenyu Dong, Norimitsu Ban, Daniel S. Ory, Rajendra S. Apte
Jonathan B. Lin, Harsh V. Moolani, Abdoulaye Sene, Rohini Sidhu, Pamela Kell, Joseph B. Lin, Zhenyu Dong, Norimitsu Ban, Daniel S. Ory, Rajendra S. Apte
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Research Article Aging Ophthalmology

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

Abstract

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.

Authors

Jonathan B. Lin, Harsh V. Moolani, Abdoulaye Sene, Rohini Sidhu, Pamela Kell, Joseph B. Lin, Zhenyu Dong, Norimitsu Ban, Daniel S. Ory, Rajendra S. Apte

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Figure 6

microRNA-150 directly targets Scd2 and thereby promotes pathological angiogenesis.

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microRNA-150 directly targets Scd2 and thereby promotes pathological ang...
(A) The 3′ untranslated region (UTR) of Scd2 contains canonical 7mer-A1 and offset 6mer microRNA-150 binding sites. (B) Cotransfection of a dual-reporter plasmid with the Scd2 3′ UTR inserted downstream of a secreted Gaussia luciferase (GLuc) reporter gene and microRNA-150 mimic led to reduced GLuc activity compared with cotransfection of the same plasmid with a negative control (NC) mimic (n = 10/group; 2-tailed, unpaired student’s t test). (C) Removing the 7mer-A1 target site (mutant 1) but not the offset 6mer target site (mutant 2) reduced the extent to which microRNA-150 cotransfection inhibited GLuc activity (n = 10/group; Kruskal-Wallis test with Dunn’s multiple comparison post-hoc test). (D and E) Adoptively transferred Scd2-deficient (Scd2KD) macrophages were less able to inhibit laser injury–induced choroidal neovascularization (CNV) compared with NC-transfected macrophages (D, representative images from n = 8–11 burns/group; 2-tailed, unpaired Welch’s t test). (F) In vitro VEGF secretion was not significantly increased in Scd2-deficient macrophages (n = 16/group; 2-tailed, unpaired Welch’s t test). (G and H) Scd2–m/–m mice exhibited larger CNV complexes after laser injury compared with Scd2f/f mice (G, representative images from n = 8–9 burns/group; 2-tailed Mann-Whitney U test). (I and J) Fasn–m/–m and Fasnf/f mice had similarly sized CNV complexes after laser injury (I, representative images from n = 8 burns/group; 2-tailed Mann-Whitney U test). Scale bars: 100 μm (D, G, I). Open circles depict individual data points; graphs depict mean ± SEM (B, E, F, H, J) (*P < 0.05; ***P < 0.001).