Mast cells (MC) are widely distributed throughout the body and are common at mucosal surfaces, a major host-environment interface. MC are functionally and phenotypically heterogeneous depending on the microenvironment in which they mature. Although MC have been classically viewed as effector cells of IgE-mediated allergic diseases, they are also recognized as important in host defense, innate and acquired immunity, homeostatic responses, and immunoregulation. MC activation can induce release of preformed mediators such as histamine from their granules, as well as release of de novo synthesized lipid mediators, cytokines and chemokines that play diverse roles, not only in allergic reactions but also in numerous physiological and pathophysiological responses. Indeed, MC release their mediators in a discriminating and chronological manner, depending upon the stimuli involved and their signaling cascades (e.g., IgE-mediated or Toll Like Receptor-mediated). However, the precise mechanisms underlying differential mediator release in response to these stimuli are poorly known. This review summarizes our knowledge of MC mediators and will focus on what is known about the discriminatory release of these mediators dependent upon diverse stimuli, MC phenotypes and species of origin, as well as on the intracellular synthesis, storage and secretory processes involved.

Summary: During neuronal‐induced inflammation, mast cells may respond to stimuli such as neuropeptides in an FcεRI‐independent manner. In this study, we characterized human mast cell responses to substance P (SP), nerve growth factor (NGF), calcitonin gene‐related peptide (CGRP) and vasoactive intestinal polypeptide (VIP) and compared these responses to human mast cell responses to immunoglobulin E (IgE)/anti‐IgE and compound 48/80. Primary cultured mast cells, generated from CD34⁺progenitors in the presence of stem cell factor and interleukin‐6 (IL‐6), and human cultured mast cells (LAD2) were stimulated with these and other stimuli (gastrin, concanavalin A, radiocontrast media, and mannitol) and their degranulation and chemokine production was assessed. VIP and SP stimulated primary human mast cells and LAD cells to degranulate; gastrin, concanavalin A, radiocontrast media, mannitol, CGRP and NGF did not activate degranulation. While anti‐IgE stimulation did not induce significant production of chemokines, stimulation with VIP, SP or compound 48/80 potently induced production of monocyte chemoattractant protein‐1, inducible protein‐10, monokine induced by interferon‐γ (MIG), RANTES (regulated on activation, normal, T‐cell expressed, and secreted) and IL‐8. VIP, SP and compound 48/80 also activated release of tumour necrosis factor, IL‐3 and granulocyte–macrophage colony‐stimulating factor, but not IL‐4, interferon‐γ or eotaxin. Human mast cells expressed surface neurokinin 1 receptor (NK1R), NK2R, NK3R and VIP receptor type 2 (VPAC2) but not VPAC1 and activation of human mast cells by IgE/anti‐IgE up‐regulated expression of VPAC2, NK2R, and NK3R. These studies demonstrate the pattern of receptor expression and activation of mast cell by a host of G‐protein coupled receptor ligands and suggest that SP and VIP activate a unique signalling pathway in human mast cells. These results are likely to have direct relevance to neuronally induced inflammatory diseases.

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.

Human mast cell (HuMC) maturation occurs in tissues interfacing with the external environment, exposing both mast cell progenitors and mature mast cells, to bacteria and their products. It is unknown, however, whether long- or short-term exposure to bacteria-derived toll-like receptor (TLR) ligands, such as lipopolysaccharide (LPS) or peptidoglycan (PGN), influences HuMC biology.