Myeloid masquerade: Microglial transcriptional signatures in retinal development and disease
Kristen M Pitts1,2, Milica A Margeta1,2
1Department of Ophthalmology, Massachusetts Eye and Ear, Harvard Medical School, Boston, MA, United States.
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.
Insights
The disease-associated microglial signature (DAM) in the central nervous system (CNS) mirrors developmental microglia, suggesting recycled gene programs in neurodegeneration. This review explores DAM
Area of Science:
- Neuroscience
- Immunology
- Ophthalmology
Background:
- Microglia are the central nervous system's (CNS) resident immune cells, crucial for neural tissue maintenance.
- The disease-associated microglial signature (DAM), or microglial neurodegenerative phenotype (MGnD), is a key response in various neurodegenerative diseases.
- DAM shares similarities with developmental microglia, indicating conserved gene programs involved in neural circuit formation, aging, and disease.
Purpose of the Study:
- To review the role of the DAM signature in retinal development and disease.
- To explore the heterogeneity of the DAM signature using single-cell RNA sequencing data.
- To highlight the interplay between microglia and infiltrating monocytes in age-related neurodegeneration.
Main Methods:
- Review of existing literature on microglia, DAM, and neurodegeneration.
- Analysis of single-cell RNA sequencing data to identify microglial heterogeneity.
- Examination of cellular crosstalk in the context of retinal aging and disease.
Main Results:
- The DAM signature is conserved across different neurodegenerative pathologies and shares features with developmental microglia.
- Single-cell RNA sequencing reveals significant heterogeneity within the DAM signature, including contributions from yolk sac-derived microglia and bone marrow-derived macrophages.
- Crosstalk between resident microglia and infiltrating monocytes is implicated in age-related neurodegeneration.
Conclusions:
- Recycled gene programs may underlie both neural development and the response to aging and neurodegenerative diseases.
- Understanding microglial heterogeneity is crucial for deciphering their role in disease.
- The interaction between microglia and monocytes is a critical factor in age-related neurodegeneration, particularly in the retina.
