Mast Cells

Mast cells are tissue-resident cells, most notably known for their role in allergy, releasing vasoactive and pro-inflammatory mediators including histamine, tryptase, proteases, prostaglandins and cytokines upon stimulation [1]. Mast cells develop from bone-marrow progenitors and mature locally within tissues, and their phenotype and function are heavily shaped by the microenvironment in which they mature [2]. Classically, they are divided into two main subsets based on protease content: mucosal mast cells, expressing tryptase, and connective tissue mast cells, co-expressing tryptase and chymase. This distinction is clearer in mice than in humans, as proteases such as Mcpt1 and Mcpt2 clearly separate mucosal mast cells from the other subset [3], while in humans the expression of the different proteases is more heterogeneous [4].

Omics technologies are currently expanding the landscape of mast cell subsets in tissues, including the gut. For instance, single-cell RNA sequencing of dissected layers of human sigmoid colon and rectal biopsies identified five transcriptionally distinct mast cell subsets with layer-specific distributions and distinct cytokine, chemokine, protease and transcription factor profiles, several with putative neuro-immune functions [5]. Cross-organ atlases and non-mast-cell-focused spatial omics studies are also useful sources of layer-resolved human gut mast cell data alongside other immune, epithelial and mesenchymal populations [6-9].

Beyond their well-known role in allergy, gut mast cells are increasingly recognised as homeostatic regulators. They help maintain epithelial barrier integrity, modulate ion and water secretion and vascular permeability, contribute to wound healing, and participate in antimicrobial defence during enteric infection through the release of TNF-α, IL-6 and other mediators, actively participating to the recruitment of innate immune cells [10,6].

Aberrant mast cell numbers, activation or mediator release have been implicated across a range of digestive diseases, including food allergy, irritable bowel disease (IBS). eosinophilic oesophagitis, gastro-oesophageal reflux disease, coeliac disease, and functional dyspepsia, in which mast cells activation affects barrier defence, motility and gut-brain crosstalk [10].

Mast cells can be activated through the canonical IgE/FcεRI pathway and through non-IgE-dependent routes, such as MRGPRX2 (mouse ortholog Mrgprb2), which responds to basic secretagogues including substance P and preferentially releases tryptase and serotonin. MRGPRX2 mRNA is upregulated in colonic biopsies of IBS subsets, though its functional contribution in the human gut remains to be established [11]. A second IgE-independent route is purinergic: ATP released during epithelial stress or infection drives degranulation through the purinergic receptor P2X7, an effect potentiated by epithelial IL-33 priming [12,13].

A defining feature of gut mast cells is their physical and functional coupling to sensory neurons. They preferentially associate with substance P- and CGRP-positive afferents [14]. The relationship is bidirectional: neuropeptides like substance P activate mast cells, while mast cell-derived mediators (histamine, serotonin, tryptase and prostaglandins) sensitise nociceptors, creating a neuro-immune feedback loop regarded as primary contributor to IBS-related abdominal pain [11]. Mechanistically, histamine acting through the H1 receptor (H1R) sensitises Transient Receptor Potential ion channels, including TRPV1, TRPV4 and TRPA1, on visceral nerve afferents, and clinically the H1R antagonist ebastine improved symptoms in IBS, supporting mast cell mediators as actionable targets [11].

From a disease standpoint, enteric infection can break oral tolerance to food allergens, producing local food-antigen-specific IgE that, on antigen re-exposure, drives mast cell- and H1R-dependent sensitisation of visceral afferents, with mucosal injection of food antigens reproducing local mast cell activation in IBS patients [15].

The most striking recent expansion of the mast cell’s remit, however, is into behaviour. Two paired animal studies showed that mucosal mast cells lining the stomach and small intestine act as the sensor cell linking antigen recognition to antigen-specific avoidance, so that sensitised mice learn to avoid an ingested allergen. Avoidance is IgE- and mast cell-dependent and precedes overt gut allergic inflammation, and allergen ingestion activates aversion-related brain regions [16,17]. The mast cell-to-brain signal requires cysteinyl leukotrienes and epithelial GDF15, reframing the mast cell as a gut sensor that drives a protective behavioural output rather than only local inflammation, positioning them as prime actors in the gut-immune-brain axis.

For functional work, gut mast cells can be studied ex vivo in mucosal biopsies and resection tissue, or as bone-marrow/peripheral-blood-derived and peritoneal cultures in mice and humans, though culture conditions and tissue of origin strongly influence protease and receptor expression, so in vitro phenotypes do not necessarily match the native gut mast cell [2]. Increasingly, intestinal epithelial organoids and enteroid-immune co-cultures are being used to reconstruct epithelial-mast cell crosstalk in a more physiological setting [18], although fully immune-competent gut organoid models remain an active development goal [19]. Human gut-derived primary mast cells remain difficult to obtain and maintain, which is part of why omics atlases of fresh human tissue are so valuable.

Text by Chiara Tontini and Silvia Bulfone-Paus, University of Manchester

 

References

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