Introduction
Although hematopoietic stem cells produce mast cell (MC) progenitors, mature MCs are normally absent in blood while found in almost all tissues as highly granulated cells. The stem cell factor (SCF) receptor, KIT, is one of the most critical receptors on mature mast cells, as a reduction in KIT signaling leads to mast cell deficiency. Yet, signaling through the receptor is redundant for early development of mast cell progenitors in peripheral blood 1. MCs are equipped with a great number of receptors enabling them to sense and react to a diversity of stimuli 2. The most studied receptor that causes MC activation is the high-affinity IgE receptor, FcεRI. Another receptor that has received particular attention during recent years is the Mas-related G protein-coupled receptor X2 (MRGPRX2), a G-protein coupled receptor recognizing a variety of pharmacologic agents (tubocurarine, atracurium, icatibant, ciprofloxacin) causing pseudo allergic reactions 3,4. MRGPRX2 also serves as receptor for substance P, components of insect venom, antimicrobial peptides, secreted eosinophil products and other cationic peptides5,6. Other receptors that induce IgE-independent MC activation include the IL-33 receptor, which is important for MCs to recognize cell injury and trauma 7 as well as regulating IgE-mediated responses 8-10, and pattern recognition receptors (PRRs) sensing “danger “ signals, including microbes 11. When MCs sense an endogenous or exogenous agent through binding to one of their many activating receptors, they react by releasing mediators through three major pathways (Figure 1). The most rapid response is exocytosis of secretory granules (SGs) and the release of preformed mediators such as histamine, proteases and heparin 12. This is accompanied by the de novobiosynthesis of lipid mediators, predominantly prostaglandin D2 (PGD2) and the cys-leukotrienes LTC4, LTD4 and LTE4, but also other lipid mediators like thromboxane A2 (TXA2) and 15-HETE 13. MCs also have the capacity to synthesize a number of cytokines, chemokines, growth factors and interferons 14. Notably, release of de novo -synthesized mediators can take place without preceding degranulation 15. Thus, MCs can be activated and produce lipid mediators and/or cytokines in the absence of detectable degranulation (by histology or measurement of granule mediators). Finally, MCs also secrete extracellular vesicles including exosomes. MC exosomes can transfer proteins, enzymes, and RNA that can be taken up by other cells, either proximal to the secreting MC or located at distant sites 16-18(www.exocarta.org) (Figure 1). Notably, patients with systemic mastocytosis have increased levels of exosomes with a MC signature including constitutively activated KIT, enabling transfer of mutant proteins to other cells 19.
Given the broad distribution of MCs and their multifunctional role, they have been implicated in many diseases beyond allergy20-22. For example, recent reviews highlight the role of MCs in cardiovascular diseases 23, cancer24, airway diseases 25, as well as in viral, bacterial and fungal infections 26-28. Even if MCs commonly are discussed in the context of disease, it is important to remember that they also have a role in homeostasis, the initiation of acute inflammation 29 and in the protection against danger, whether it comes from the outside (venoms, pathogens, etc.) or from within the body (cell injury etc.) 30.
In this review we highlight some of the most recent findings regarding MC origin and development, recruitment, heterogeneity and reactivity, MC disease, new therapeutic possibilities, and animal models to study MC biology.