Abstract
Microglia, resident immune cells of the central nervous system (CNS), play a pivotal role in immune surveillance and maintenance of neuronal health. Mast cells are also important resident immune cells of the CNS but they are underappreciated and understudied. Both microglia and mast cells are endowed with an array of signaling receptors that recognize microbes and cellular damage. As cellular sensors and effectors in the CNS, they respond to many CNS perturbations and have been implicated in neuroinflammation and neurodegeneration. Mast cells contain numerous secretory granules packaged with a plethora of readily available and newly synthesized compounds known as ‘mast cell mediators’. Mast cells act as ‘first responders’ to a pathogenic stimuli and respond by degranulation and releasing these mediators into the extracellular milieu. They alert other glial cells, including microglia to initiate neuroinflammatory processes that culminate in the resolution of injury. However, failure to resolve the pathogenic process can lead to persistent activation, release of pro-inflammatory mediators and amplification of neuroinflammatory responses, in turn, resulting in neuronal dysfunction and demise. This review discusses the current understanding of the molecular conversation between mast cells and microglia in orchestrating immune responses during two of the most prevalent neurodegenerative diseases, namely Alzheimer’s disease and Parkinson’s disease. Here we also survey the potential emerging therapeutic approaches targeting common pathways in mast cells and microglia to extinguish the fire of inflammation.
Highlights
Innate Immune System of the BrainThe innate immune system is the first line of defense that protects the central nervous system (CNS) against exogenous pathogens, including viruses, bacteria, fungi, protozoans and parasites and endogenous sterile molecules, including abnormal misfolded forms of proteins such as βamyloid and α-synuclein [17]
Introduction iationsThe most common pathological manifestations of age-related neurodegenerative diseases are the extracellular accumulation of misfolded aggregated proteins, such as β-amyloid and α-synuclein, and a progressive loss of vulnerable populations of neurons in specific brain regions [1]
Microglia deploy gene products involved in chemotaxis (CX3CR1), phagocytosis (Triggering Receptor Expressed on Myeloid cells 2 (TREM2) and scavenger receptors) and synaptic pruning and remodeling (C1q and CX3CR1) [49]
Summary
The innate immune system is the first line of defense that protects the CNS against exogenous pathogens, including viruses, bacteria, fungi, protozoans and parasites and endogenous sterile molecules, including abnormal misfolded forms of proteins such as βamyloid and α-synuclein [17]. Mast cells can be activated by a wide range of immunological and non-immunological stimuli (DAMPs, such as amyloid-β and α-synuclein) and act as the cellular sensors of the innate immune system [40,41]. Autocrine production of some of these mediators can subsequently inhibit further mast cell activation, thereby leading to resolution of the inflammatory response [43], but these mediators can act in a paracrine manner, reaching a distance of over 50 μm from the cell body in the mouse brain. Similar to their role in other tissues, mast cells may activate and orchestrate the behaviors of the other brain immune cells such as astroglia and microglia and thereby regulate neuroinflammatory responses in the CNS
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