Researchers here provide evidence for microRNA-150 to be a part of the regulatory machinery that determines whether macrophage behavior is inflammatory and damaging, or regenerative and helpful. This is part of a most interesting line of research that examines the various polarizations of macrophages, a polarization being a class of behavior and activity, and their contribution to age-related disease. As aging progresses, an ever large fraction of the macrophage population in many tissues becomes inflammatory and aggressive, hindering regeneration, or promotes unhelpful functions in tissue, such as excessive growth of blood vessels. The exact chain of cause and effect that lies between the known root causes of aging and macrophage dysfunction is yet to be determined, but researchers are making progress in mapping mechanisms that might be used to force macrophages to be less damaging in older individuals.
Macrophages are critical effector cells of the innate immune system. Multiple groups, including our own, have reported that macrophages from aged mice demonstrate a functional drift compared with those isolated from young mice. For example, aged macrophages exhibit epigenomic changes, leading to reduced autophagic capacity, and are defective in their ability to fight viral infections due to reduced phagocytic activity. Moreover, aged macrophages are skewed toward a proangiogenic gene and cytokine expression profile, which leads to dysregulated inflammation and the inability to inhibit pathological angiogenesis. Aged macrophages also exhibit impaired cholesterol efflux due to decreased Abca1 expression, leading to intracellular cholesterol accumulation and pathologic vascular proliferation. Age-associated macrophage dysfunction has been proposed to contribute to the pathogenesis of numerous diseases of aging, including age-related macular degeneration (AMD) and atherosclerosis. In addition, age-associated changes in microglia, the major resident immune cell in the retina with similar phagocytic functions, may also promote AMD.
AMD is a leading cause of blindness in industrialized nations and displays a complex disease course characterized, initially, by accumulation of cholesterol-rich deposits known as drusen underneath the retina. Though drusen themselves do not typically cause vision loss, they are risk factors for progression to one of 2 forms of advanced AMD: advanced neovascular (wet) AMD, characterized by pathologic subretinal angiogenesis, or advanced dry AMD, characterized by geographic atrophy secondary to loss of retinal neurons and underlying cells. Both forms of advanced AMD can cause debilitating blindness, though wet AMD causes a significant portion of the vision loss associated with AMD.
There is support for the idea that impaired cholesterol homeostasis contributes to AMD pathogenesis. Impaired cholesterol homeostasis also contributes to the pathogenesis of atherosclerosis. Atherosclerotic plaque formation begins when circulating monocytes adhere to the vascular endothelium, migrate to the sub-endothelial space, and activate into macrophages that take up lipids and become foam cells. Past studies have demonstrated that the activation/polarization state of macrophages is important for predicting plaque phenotype and stability. For example, in patients with hypercholesterolemia, macrophages polarize to a more proinflammatory state, which could predispose to plaque formation. Remarkably, atherosclerotic plaques and drusen have similar lipid compositions, unifying the pathogenic pathways underlying these diseases. Based on these similarities, some have proposed that it may be possible to repurpose statins, lipid-lowering drugs used to treat atherosclerosis, for treating AMD.
Despite these advances in our understanding of the phenotype of aged macrophages and how such changes contribute to age-associated diseases, the molecular mechanisms by which macrophages drift toward the disease-promoting phenotype remain elusive. Given the immense spectrum of these changes in aged macrophages, we hypothesized that microRNAs (miRs) may regulate the transcriptome of macrophages and, thereby, the transition of macrophages to a disease-promoting phenotype. The ability of miRs to target multiple genes makes them strong candidates as molecular regulators.
In this study, we sought to identify one or more miRs that regulate the disease-promoting programmatic changes in macrophages that are associated with AMD. Our results demonstrate that miR-150 is highly upregulated both in disease-promoting murine macrophages and in human peripheral blood mononuclear cells (PBMCs) from AMD patients. Moreover, we show that miR-150 regulates macrophage-mediated inflammation and pathologic angiogenesis, suggesting that it regulates the transition of macrophages from a healthy profile to the AMD-promoting phenotype. Ultimately, these findings provide insight into the mechanisms underlying the pathological programmatic changes in aged macrophages and may lead to the identification of novel therapeutic targets and candidate biomarkers.