Mast cells are primitive immune cells that appear early in evolution and have since evolved into multifunctional cells in vertebrates.1 They have been long recognized as initiators of IgE-dependent allergic diseases but it is now realized that they also play a fundamental role in innate and adaptive immune responses to infection as well as inflammatory autoimmune diseases.2–4 In addition, there is evidence that mast cells participate in inflammatory responses to incipient tumors which may either facilitate or retard tumor growth depending on the type of cancer.5–7 Other suspected non-immunological roles for mast cells include promotion of angiogenesis, tissue remodeling, and wound healing.8–11 As such, mast cells occupy a precarious position in that their responses to endogenous and exogenous stimuli can be detrimental as well as beneficial to the host.
The scope of the physiologic and pathologic roles noted above illustrate the flexible nature of mast cells which is enabled in part by their ability to release a broad array of bioactive mediators, either preformed and stored in granules such as histamine and proteases, or newly generated such as eicosanoids, cytokines, and chemokines.12–14 Mast cells also exhibit phenotypic plasticity which is manifested by differential expression of receptors and granule constituents. The localization of mast cells in tissues as well as their replication and differentiation into distinct phenotypes are typically determined by the chemical environment of their final tissue destination.1, 13, 15 KIT ligand (stem cell factor or SCF) is critical for these processes although other growth and chemotactic factors are necessary. Flexibility in function is also conferred through expression of multiple types of receptors.14 These include Fc, cytokine, tyrosine kinase, and trimeric G protein-coupled receptors.12, 16 In addition, mast cells can respond to microbial products through pattern recognition receptors (PRR) which include the Toll-like receptors (TLRs) and the recently recognized nucleotide-binding oligomerization domain (NOD)-like receptor (NLRs).17 These two families of receptors recognize pathogen-associated molecular patterns (PAMPs) of microbial origin and include both cytosolic and surface-expressed receptors. Many of these receptors can act in concert with the IgE receptor, FcεRI, to substantially enhance mast cell responses to antigens or alter the pattern of response such that production of cytokines, for example, predominates over degranulation.18, 19 Moreover, mast cells can be negatively regulated through immunoreceptor tyrosine-based inhibitory motif (ITIM)-bearing receptors such as FcγRIIb, gp49B1, signal regulatory protein-α (SIRPα), the transforming growth factor-β (TGFβ) receptor, along with the non-ITIM-bearing receptor such as CD200.20, 21
All of the above features likely underlie the multifunctional nature of mast cells but little specific information is available as to how mast cells adapt in different immunological/pathological settings even though it is now evident that the relative composition and amount of mediators released from activated mast cells, and the degree to which they home to sites of inflammation, can be profoundly influenced by the extent to which surface receptors interact to engage alternative and complementary intracellular signaling pathways. Therefore, mast cell activation in health and diseases states should be considered in the context of co-stimulatory and inhibitory factors present in the surrounding tissue milieu and not just in terms of specific allergen-mediated processes. In the following sections we review studies that demonstrate potentiation or suppression of FcεRI-induced responses by activating or inhibitory receptors and the regulation of expression of these receptors by endogenous factors. Although most of these studies were conducted with mast cells in culture, they begin to provide insights as to how mast cell function might be modulated in situ. Our intent is to foster further interest in the interplay among mast cell receptors to create a sufficient body of evidence to provide mechanistic explanations for each of the immunological and non-immunological functions attributed to mast cells. Because of the impact on clinical practice, we also discuss receptor-independent mechanisms of mast cell activation by mast cell “secretagogues”, a category that includes opiates and other drugs in addition to antidotes to the biological effects of mast cell products. Finally, we assess the pathophysiologic roles of mast cells and their products in health and disease.