Role of macrophage microRNA-150 in age-related macular degeneration

Abstract

Purpose : Age-related macular degeneration (AMD) is a leading cause of blindness in adults over 50 years of age in industrialized countries. We and others have reported that aged macrophages exhibit functional changes in their activation status and in their ability to maintain cholesterol homeostasis and thereby promote AMD. However, the role of microRNAs (miRs) in regulating these AMD-promoting functional shifts in aged macrophages is underexplored. The goal of this study was to identify the miRs that coordinate the transcriptomic changes in macrophages that promote AMD pathogenesis and cause blindness.

Methods : To identify miRs that promote the transition of macrophages to the AMD-promoting phenotype, we performed a miR microarray, comparing macrophages from 6-8-week-old mice and 18-month-old wild-type mice. We then examined the cellular phenotype associated with miR-150 overexpression by RNA-Sequencing followed by pathway analysis for enriched gene ontology (GO) processes, process networks, and pathway maps with MetaCore. To validate the translational relevance of our findings, we quantified miR-150 levels in the peripheral blood mononuclear cells (PBMCs) of human AMD patients (N = 43) and control subjects without AMD (N = 63). For all analysis, we considered P < 0.05 to be statistically significant.

Results : MiR-150 had the highest fold changes in aged macrophages with ~9-fold higher expression in old peritoneal macrophages (P < 0.0001), ~3-fold higher expression in old splenic macrophages (P < 0.01), and ~3-fold higher expression in old bone marrow-derived macrophages (P < 0.05). Macrophages overexpressing miR-150 exhibited an altered transcriptomic profile enriched for the pathway map of aberrant lipid trafficking and metabolism in AMD pathogenesis (P=4.4×10^-5; FDR=5.5×10^-3). AMD patients had significantly higher PBMC miR-150 levels compared to control subjects (P < 0.0001). A gender- and age-adjusted binary logistic regression model confirmed that a ten-fold increase in PBMC miR-150 levels was associated with a 29.0-fold increased odds of having AMD (95% CI: 5.9-141.5).

Conclusions : Our results demonstrate that miR-150 is upregulated in AMD-promoting macrophages and implicate miR-150 as pathogenic in AMD. Ultimately, our results identify not only potential therapeutic targets for modulating the transition to the aged macrophage phenotype but also a potential biomarker for monitoring AMD progression.

This is an abstract that was submitted for the 2018 ARVO Annual Meeting, held in Honolulu, Hawaii, April 29 - May 3, 2018.