Epigenetic and transcriptional control of mast cell responses

Abstract

Mast cells are tissue-resident, innate immune cells present in most tissues of the body and are important effector and immunomodulatory cells. Differentiated mast cells typically are characterized by the surface expression of the receptors KIT and FcεRI, the latter especially being important for stimulation through IgE antibodies, although these cells have the ability to respond to a wide variety of environmental signals, to which they can variably react by releasing pre-stored or de novo-synthesized mediators or both. Since mast cells terminate their differentiation in their tissue of residence in response to specific microenvironmental cues, each tissue may comprise unique mast cell subtypes, and responses are tailored to the danger signals that are likely to be encountered in each anatomical location. From a transcriptional point of view, these cells therefore must be endowed with epigenetic and transcriptional programs that allow them to maintain a stable identity and at the same time allow sufficient plasticity to adapt to different environmental challenges. In this commentary, we highlight some of the recent findings that advanced our understanding of the transcriptional and epigenetic programs regulating mast cell functions.

Keywords: epigenetic control; mast cell response; transcription factors.

Figure 1.. Mast cells and their receptors.

Mast cells are highly reactive cells expressing a plethora of receptors with specificity toward many types of stimuli. Upon activation, mast cells can release pre-formed mediators stored in cytoplasmic granules, including proteases and vasoactive mediators, while cytokines and chemokines can be either pre-stored or de novo–synthesized. The most commonly studied pathway for mast cell activation includes the engagement of the high-affinity IgE receptor (FcεRI), and is dependent on the production of antigen-specific IgE antibodies by B lymphocytes, in response to interleukin-4 (IL-4) and IL-13 produced by T helper 2 (Th2) lymphocytes . Crosslinking of the FcεRI-bound IgE by antigens results in mast cell degranulation and cytokine production . Mast cells can also express surface receptors for IgG antibodies, namely FcγR, whose engagement can lead to both activating and inhibitory signals, depending on the specific receptor involved . A variety of pathogen recognition receptors (PRRs), including Toll-like receptors (TLRs), are also expressed on the mast cell surface. For example, TLR2 is activated by bacterial lipopeptides, while TLR4 is activated by lipopolysaccharide (LPS) binding. Notably, TLR-mediated activation does not usually lead to mast cell degranulation, but triggers the production of de novo–synthetized mediators such as cytokines and chemokines. Mast cells also express receptors for chemokines, cytokines, and growth factors, essential not only for their maturation and differentiation but also to modulate their responses. For example, the KIT receptor binds the stem cell factor (SCF), important for mast cell proliferation and maturation . The MRGPRX2 receptor is activated by a range of ligands, including inflammatory peptides and drugs associated with allergic reactions . Finally, complement receptor-mediated activation of mast cells can be induced by different complement components, such as C3a or C5a . Transcription factors such as PU.1, MITF, GATA and C/EBP family members have critical roles in regulating mast cell development and in the maintenance of cell identity , while transcription factors such as NF-κB, NFAT and AP-1 are predominantly involved in the acute regulation of inflammatory genes .

Figure 2.. Mast cell–related disorders.

Diseases associated with mast cells can broadly include disorders associated with extrinsic factors, such as the ones mediated by IgE antibodies that, acting through the high-affinity IgE receptor (FcεRI) expressed on the mast cell surface, can translate into the development of allergic reactions. Allergies are detrimental immune responses against otherwise innocuous environmental antigens, which induce the production of IgE antibodies that can activate mast cells, eventually leading to, for example, allergic rhinitis, asthma, and atopic dermatitis . Excessive allergic reactions can translate into anaphylaxis. Other disorders can instead be cell-intrinsic, due to altered biological features of mast cells that lead to uncontrolled responses (mast cell activation syndrome, or MCAS) or excessive proliferation (systemic and cutaneous mastocytosis, or SM and CM). Potentially, all mast cell disorders can display altered activation and are broadly defined as mast cell activation disorders (MCADs), although MCAS represents a subgroup displaying mast cell activation without clonal expansion ^, .

Figure 3.. DNA methylation dynamics.

( a) Mechanisms of maintenance and loss of DNA methylation. During DNA replication, DNMT1 binds hemi-methylated single-stranded DNA (ssDNA) and copies DNA methylation patterns on the newly synthetized DNA strand, thereby maintaining the overall DNA methylation landscape across DNA replication and cell division. In the absence of DNMT1, such a process is impaired, resulting in the passive dilution of the methyl mark during cell division. While DNMT1 acts as the primary maintenance DNMT enzyme during cell division, DNMT3A and DNMT3B also contribute to DNA methylation as de novo DNMTs (namely they do not require a hemi-methylated DNA template but also can act on fully unmethylated DNA). ( b) DNA methylation and hydroxymethylation. DNMT enzymes methylate the 5′ carbon residue on the cytosine ring in DNA, giving rise to 5′-methylcytosine (5mC). Iterative oxidation of the methyl group mediated by ten-eleven-translocation (TET) enzymes leads to the formation of 5′-hydroxymethylcytosine, followed by 5′-formylcytosine and 5′-carboxylcytosine. The latter two modifications are recognized and excised by the thymine-DNA-glycosylase (TGD) enzyme, leaving an abasic site in the DNA, which is repaired by base excision repair (BER) mechanisms. Because this process of iterative oxidation leads to the substitution of a modified cytosine with an unmodified one, it is also termed TET protein-assisted active DNA demethylation.