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.