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 5

microRNA-150 modulates fatty acid synthase (Fasn) and stearoyl-CoA desaturase-2 (Scd2) expression.

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microRNA-150 modulates fatty acid synthase (Fasn) and stearoyl-CoA desat...
(A and B) Eight of the 26 putative microRNA-150 targets had decreased expression in aged macrophages (n = 6-12/group; 2-tailed, unpaired Welch’s t test). (C and D) microRNA-150 mimic–transfected macrophages had reduced expression of Fasn and Scd2 compared with nontargeting negative control-transfected (NC-transfected) macrophages (n = 12/group; 2-tailed, unpaired student’s t test). (E and F) Macrophages transfected with Fasn- and Scd2-targeting small-interfering RNA (siRNA) had reduced expression of target genes (n = 4-5/group; 2-tailed, unpaired student’s t test; KD, knock down). (G and H) Fasn-deficient (FasnKD) macrophages were somewhat abnormally activated but had normal expression of proangiogenic factors (n = 14/group; 2-tailed, unpaired Welch’s t test). (I and J) Scd2-deficient (Scd2KD) macrophages were abnormally activated and had increased expression of proangiogenic factors (n = 10/group; 2-tailed, unpaired Welch’s t test). Open circles depict individual data points; graphs depict mean ± SEM (C–F) (*P < 0.05; **P < 0.01; ***P < 0.001; #P < 0.0001).