The transcriptional program, functional heterogeneity, and clinical targeting of mast cells

Abstract

Mast cells are unique tissue-resident immune cells that express an array of receptors that can be activated by several extracellular cues, including antigen-immunoglobulin E (IgE) complexes, bacteria, viruses, cytokines, hormones, peptides, and drugs. Mast cells constitute a small population in tissues, but their extraordinary ability to respond rapidly by releasing granule-stored and newly made mediators underpins their importance in health and disease. In this review, we document the biology of mast cells and introduce new concepts and opinions regarding their role in human diseases beyond IgE-mediated allergic responses and antiparasitic functions. We bring to light recent discoveries and developments in mast cell research, including regulation of mast cell functions, differentiation, survival, and novel mouse models. Finally, we highlight the current and future opportunities for therapeutic intervention of mast cell functions in inflammatory diseases.

Figure 1.

Evolutionary adaptations of mast cell functions. Mast cell–derived mediators are critically involved in the detoxification of arthropod and reptile venoms. For example, whereas CPA3 is involved in the inhibition of Sarafotoxin 6B, MCPT4 is critical for the inhibition of Helodermin. Mast cells also contribute to the T_h2-type immune response, which is critical for the prevention of helminth infections.

Figure 2.

Epigenetic control of mast cell homeostasis. DNA methyltransferase DNMT3a is involved in de novo DNA methylation in CpG regions, which is important for gene expression regulation and homeostasis in mast cells. DNMT3a-deficient mouse mast cells are hyper-responsive to FcεR1 cross-linking and release increased mediators and cytokines. TET2, however, converts 5-mC to 5-hmC in DNA. TET2 functions are also important for mast cell proliferation and mediator release. TET2-deficient mouse mast cells are impaired in differentiation, but they have elevated proliferative capacity in culture. Importantly, TET2 mediates both enzymatic activity–dependent and independent functions in mast cells. Mast cell protease tryptase is another epigenetic regulator in mast cells. Nuclear tryptase is involved in the clipping of histone H2 and H3. Notably, tryptase deficiency results in increased H2BK5ac levels in non–mast cell genes.

Figure 3.

Different modes of mast cell activation. Mast cell identity is maintained by the coordinated actions of several TFs such as MITF, GATA-2, STAT-5, and ATF-3. Mast cells can be activated by different GPCRs such as MRGPRX2 and high-affinity IgE receptor FcεR1. However, there are notable differences between MRGPRX2- and FcεR1-mediated mast cell activation. Although ligand binding to MRGPRX2 leads to intracellular calcium increase and degranulation, there is very limited cytokine response. However, high-affinity antigen-mediated FcεR1 cross-linking involves higher intracellular calcium levels, degranulation, and inflammatory cytokine and chemokine response involving various TFs such as NF-κB, NFAT, AP-1, EGR1, and EGR2. Despite similar levels of FcεR1 receptor phosphorylation, low-affinity antigen-mediated FcεR1 cross-linking involves a smaller increase in intracellular calcium levels and degranulation, and the inflammatory response is more chemokine based compared with high-affinity antigen-mediated activation. This is due to the involvement of cytoplasmic Fgr kinase and the membrane-bound LAT2 adaptor. Finally, although cytoskeleton rearrangements such as microtubule polymerization and actin depolymerization are a common feature of all forms of degranulation, the components of SNARE machinery are less well known in MRGPRX2-mediated degranulation.

Figure 4.

Clinical targeting of mast cell functions. There are various extracellular cytokines that are released from mast cells or that regulate the mast cell responses after binding to their corresponding receptors on mast cells. Some of these cytokines have been targeted using blocking monoclonal antibodies, which are in use to treat allergic disorders such as asthma. These cytokines include TNF, IL-1, IL-5, IL-9, IL-13, IL-17A, IL-33, GM-CSF, and thymic stromal lymphopoietin (TSLP). Furthermore, extracellular IgE is targeted with Omalizumab, and histamine is targeted with antihistamines. Similarly, many cell-surface receptors involved in mast cell activation are also therapeutic targets. These receptors include IL-4Rα (a common receptor for IL-4 and IL-13), cysteinyl leukotriene receptor 1 (CYSLTR1), and β-2 adrenergic receptor (ADRB2). Intracellular targets in mast cells include Syk kinase (mediating LAT phosphorylation and signal propagation), intracellular calcium, arachidonate 5–lipoxygenase (ALOX5; important for leukotriene synthesis), cyclooxygenase 2 (COX-2; important for prostaglandin synthesis), calcineurin (phosphatase activating NFAT TF), and the glucocorticoid receptor (inhibiting proinflammatory cytokine synthesis). Inhibitory receptor Siglec 8 is also another therapeutic target. Promising future therapies might also include the use of antisense oligonucleotides, DNAzymes, and small-molecule inhibitors of MRGPRX2 receptor activation.