Bidirectional Interplay Between Microglia and Mast Cells

Abstract

Microglia, the brain's resident innate immune cells, play a fundamental role in maintaining neural homeostasis and mediating responses to injury or infection. Upon activation, microglia undergo morphological and functional changes, including phenotypic switching between pro- and anti-inflammatory types and the release of different inflammatory mediators. These processes contribute to neuroprotection and the pathogenesis of various central nervous system (CNS) disorders. Mast cells, although sparsely located in the brain, exert a significant influence on neuroinflammation through their interactions with microglia. Through degranulation and secretion of different mediators, mast cells disrupt the blood-brain barrier and modulate microglial responses, including alteration of microglial phenotypes. Notably, mast cell-derived factors, such as histamine, interleukins, and tryptase, activate microglia through various pathways including protease-activated receptor 2 and purinergic receptors. These interactions amplify inflammatory cascades via various signaling pathways. Previous studies have revealed an exceedingly complex crosstalk between mast cells and microglia suggesting a bidirectional regulation of CNS immunity, implicating their cooperation in both neurodegenerative progression and repair mechanisms. Here, we review some of the diverse communication pathways involved in this complex interplay. Understanding this crosstalk may offer novel insights into the cellular dynamics of neuroinflammation and highlight potential therapeutic targets for a variety of CNS disorders.

Keywords: PAR2; cytokines; histamine; mast cells; microglia; neuroinflammation; purinergic receptors.

Figure 1

Interactions between mast cells and microglia in the brain. Bidirectional communication may influence not only the release of different mediators but also impact the state of activation of these immune cells. Microglial phenotype switching is influenced by signals arising from their environment. Activated mast cells could be a source of these mediators. Mast cell-derived factors, like different interleukins, trypsin, tryptase, or histamine, trigger the alteration of the microglial phenotype to switch either to M1 pro-inflammatory or M2 anti-inflammatory subclasses. Both the M1 and M2 phenotypes can be characterized by a specific spectrum of pro- or anti-inflammatory mediator release leading to neuroinflammation or tissue repair, respectively. Activated microglia may then affect mast cell activation, resulting in a more prominent inflammatory response. FcεR1: high-affinity immunoglobulin E (IgE) receptor, TLR4: toll-like receptor 4, IL: interleukin, PAR2R: protease-activated receptor 2, P2XR: purinergic P2 receptor, H1R/H4R: histamine receptor 1 and 4, TNF-α: tumor necrosis factor-α, TGF-β: transforming growth factor-β, BDNF: brain-derived neurotrophic factor, PGE2: prostaglandin E2, NO: nitric oxide, ROS: reactive oxygen species.

Figure 2

Graphical representation of the main signaling pathways between mast cells and microglia involving PAR2, purinergic, and histaminergic signaling. Activated mast cells release tryptase, which cleaves PAR2R and induces signal transduction pathways via MAPK/Erk and p38 MAPK activation. ATP is a ubiquitous mediator that, in addition to appearing extracellularly in the brain as a result of physiological neuronal activity or neuronal tissue damage, is also released during inflammatory processes by several tissue elements, including mast cells. ATP targets both microglia and mast cells acting through various purinergic receptors such as the cation channel P2X4R or P2X7R. Histamine has a dual action on microglia, inducing the release of both pro- and anti-inflammatory mediators through histamine receptors H1R and H4R. All induced signal transduction pathways regulate microglia phagocytic function and motility. MCP 1: monocyte chemoattractant protein-1, PAR2: protease-activated receptor 2, H1R/H4R: histamine receptor 1 and 4, NO: nitric oxide, iNOS: inducible NO synthase, IL: interleukin, TNF: tumor necrosis factor, BDNF: brain-derived neurotrophic factor, ROS: reactive oxygen species, infl.: inflammatory.