Microglia mediated neuroinflammation in neurodegenerative diseases: A review on the cell signaling pathways involved in microglial activation

Microglia, the immune sentinels of the central nervous system (CNS), have emerged to be the central players in many neurological and neurodegenerative diseases. Recent studies on large genome databases and omics studies in fact provide support to the idea that microglial cells could be the drivers of these diseases. Microglial cells have the capacity to undergo morphological and phenotypic transformations depending on its microenvironment. From the homeostatic ramified state, they can shift their phenotypes between the two extremes, known as the proinflammatory M1 and anti-inflammatory M2 phenotype, with intermediate transitional states, characterized by different transcriptional signature and release of inflammatory mediators. The temporal regulation of the release of the inflammatory factors are critical for damage control and steering the microglia back towards homeostatic conditions. A dysregulation in these can lead to excessive tissue damage and neuronal death. Therefore, targeting the cell signaling pathways that are the underpinnings of microglial modulations are considered to be an important avenue for treatment of various neurodegenerative diseases. In this review we have discussed various signaling pathways that trigger microglial activation from its ramified state and highlight the mechanisms of microglia-mediated neuroinflammation that are associated with various neurodegenerative diseases. Most of the cellular factors that drive microglia towards a proinflammatory phenotype are components of the immune system signaling pathways and cell proliferation, along with certain ion channels. The anti-inflammatory phenotype is mainly elicited by purinoceptors, metabolic receptors and other receptors that primarily suppress the production proinflammatory mediators.