Myeloid masquerade: Microglial transcriptional signatures in retinal development and disease

Abstract

Microglia are dynamic guardians of neural tissue and the resident immune cells of the central nervous system (CNS). The disease-associated microglial signature (DAM), also known as the microglial neurodegenerative phenotype (MGnD), has gained significant attention in recent years as a fundamental microglial response common to various neurodegenerative disease pathologies. Interestingly, this signature shares many features in common with developmental microglia, suggesting the existence of recycled gene programs which play a role both in early neural circuit formation as well as in response to aging and disease. In addition, recent advances in single cell RNA sequencing have revealed significant heterogeneity within the original DAM signature, with contributions from both yolk sac-derived microglia as well as bone marrow-derived macrophages. In this review, we examine the role of the DAM signature in retinal development and disease, highlighting crosstalk between resident microglia and infiltrating monocytes which may critically contribute to the underlying mechanisms of age-related neurodegeneration.

CD11c-expressing microglia are transient, driven by interactions with apoptotic cells

“…We previously found that murine retinal microglia gene expression is heterogeneous and dynamic throughout development (5, 6). Notably, we showed that a majority of microglia early in postnatal retina express CD11c (Integrin αX, complement receptor 4, Itgax ) and were remarkably similar to CD11c-expressing (CD11c+) microglia of the developing and diseased brain (6, 7). By single-cell RNA sequencing, we found heterogeneity in CD11c+ microglia, but all CD11c+ microglia expressed genes associated with phagocytosis and lysosomal function (6).…”

Glial metabolic alterations during glaucoma pathogenesis

“…The mechanisms and consequences of inflammation in glaucoma are well documented and will not be a focus of this review. For more detailed information about the influence of microglial ( 72 – 75 ), astrocyte ( 76 ), Müller cells ( 77 ), complement ( 78 , 79 ) and oxidative stress ( 78 ), immune signalling or inflammation in general ( 80 , 81 ) on glaucoma pathology, we direct the reader to other reviews. While inflammatory signalling mechanisms are well understood, we know very little about what metabolic changes occur because of, or even preceding, these inflammatory reactions.…”