Transcriptional and epigenetic regulation of microglia in maintenance of brain homeostasis and neurodegeneration

Abstract

The emerging role of microglia in brain homeostasis, neurodegeneration, and neurodevelopmental disorders has attracted considerable interest. In addition, recent developments in microglial functions and associated pathways have shed new light on their fundamental role in the immunological surveillance of the brain. Understanding the interconnections between microglia, neurons, and non-neuronal cells have opened up additional avenues for research in this evolving field. Furthermore, the study of microglia at the transcriptional and epigenetic levels has enhanced our knowledge of these native brain immune cells. Moreover, exploring various facets of microglia biology will facilitate the early detection, treatment, and management of neurological disorders. Consequently, the present review aimed to provide comprehensive insight on microglia biology and its influence on brain development, homeostasis, management of disease, and highlights microglia as potential therapeutic targets in neurodegenerative and neurodevelopmental diseases.

Keywords: brain homeostasis; brain immunity; epigenetic changes; microglia; neurological diseases; transcription factors.

Figure 1

Molecular interaction of microglia with brain cells: (A) Microglia-Neuronal interactions; (B) Microglia-Astrocyte interaction; (C) Microglia-Oligodendrocyte interactions; and (D) Microglia-Cerebrovascular endothelial cells interactions.

Figure 2

Microglial activation pathways in neuroprotection and neurodegeneration. (A) Classical Pathway: PAMPs/DAMPs activate TLRs such as TLR-4 on resting microglia and result in a phenotypic transition to M1 type microglia and secrete pro-inflammatory factors having neurotoxic functions. Alternative pathway: Factors such as IL-4 and IL-13 modulates the transition of microglia to M2 phenotype and provide neuro-protective function by secreting anti-inflammatory cytokines. (B) Diagrammatic representation showing molecular changes in homeostatic microglia leads to their conversion in disease associated microglia phenotype during neurodegeneration.

Figure 3

Microglial activation is involved in the progression of neurodevelopmental and degenerative diseases. During pathological processes, alternation in microglial function and activation process is involved in neurodegenerative diseases such as (A) Alzheimer’s disease (AD), (B) Multiple Sclerosis (MS), (C) Amyotrophic Lateral Sclerosis (ALS), and (D) Parkinson’s Disease (PD) as well as (E) neurodevelopmental diseases.