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Review

Insights into the Characteristics and Functions of Mast Cells in the Gut

by
Yuexin Guo
1,†,
Boya Wang
2,†,
Han Gao
3,4,
Chengwei He
3,
Shuzi Xin
3,
Rongxuan Hua
3,
Xiaohui Liu
3,
Sitian Zhang
3 and
Jingdong Xu
3,*
1
Department of Oral Medicine, Beijing Stomatological Hospital, Capital Medical University, Beijing 100050, China
2
Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Department of Gastrointestinal Oncology, Peking University Cancer Hospital & Institute, Beijing 100142, China
3
Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Capital Medical University, Beijing 100069, China
4
Department of Clinical Laboratory, Aerospace Center Hospital, Peking University, Beijing 100049, China
*
Author to whom correspondence should be addressed.
†
These authors contributed equally to this work.
Gastroenterol. Insights 2023, 14(4), 637-652; https://doi.org/10.3390/gastroent14040043
Submission received: 21 August 2023 / Revised: 1 November 2023 / Accepted: 14 November 2023 / Published: 5 December 2023
(This article belongs to the Section Gastrointestinal Disease)
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Abstract

:
Mast cells have vital functions in allergic responses and parasite ejection, while the underlying mechanisms remain unclear. Meanwhile, MCs are essential for the maintenance of GI barrier function, and their interactions with neurons, immune cells, and epithelial cells have been related to various gastrointestinal (GI) disorders. An increasing number of investigations are being disclosed, with a lack of inner connections among them. This review aims to highlight their properties and categorization and further delve into their participation in GI diseases via interplay with neurons and immune cells. We also discuss their roles in diseases like inflammatory bowel disease (IBD) and irritable bowel syndrome (IBS). Based on the evidence, we advocated for their potential application in clinical practices and advocated future research prospects.

1. Introduction

Mast cells have caught scientists’ curiosity since their discovery in 1878 as essential subsets of immune cells present in a variety of organs and tissues [1]. Its distribution in vascular tissues as well as the connective tissues of the organ mucosa is of particular concern [2]. Unlike other hematopoietic-derived cells, MCs bear more resemblance to macrophages and differentiate from yolk sac and bone marrow precursors [3]. Further differentiation occurs in adjacent tissues under stimulation, where they secrete granules and initiate immunological responses and cell proliferation [4]. In the meantime, they could phagocytose bacteria and particles in response to Toll-like receptors (TLRs) [5,6]. Monoclonal antibody Ki-MC1 is recognized as one marker of mast cells, and more detailed classifications are also put forward to distinguish different functional subgroups of them [7,8]. Two common subgroups of mast cells include mucosal mast cells (MMCs) and connective tissue mast cells (CTMCs), which possess high immune similarity but differ in growth rate [9] as well as mast cell proteases (MCP) expression profiles [10].
The gastrointestinal (GI) system is the largest immune organ in the human body and a crucial location for food digestion [11]. GI diseases differ from one another and have substantial impacts on patient life quality. However, most current therapies are symptomatic, with patients waiting for more comprehensive and complete healing [12]. Meanwhile, most GI diseases exhibit alterations in GI neurons [13,14]. As a significant hub between the nervous system and the immune system, mast cells are of particular importance in the interaction between pathological inflammation and clinical discomfort. IBD and IBS are typical diseases in the GI system, and the involvement of mast cells and the production of numerous bioactivators are reported in these diseases [15]. Considering the intimate connections of mast cells with the GI microorganism and the nervous system, improved understandings of them would be extremely beneficial in promoting optimal therapy for gastrointestinal diseases [15,16].
After analyzing the biological properties of mast cells in the gastrointestinal tract, we clarified essential roles of mast cells in maintaining the GI epithelial barrier. Furthermore, we summarized the roles of mast cells in the immune system and neuroinflammation. Specifically, we provide in-depth descriptions of the mast cells involvement in complications.

2. Biological Characteristics of Mast Cells in the Gastrointestinal Tract

Mast cells are distributed throughout the body and are abundant in the GI [17]. With a mean diameter of 12.6–13.5 μm, they can vary in morphology between organs [18]. Agents like compound 48/80 have the potential to degranulate 50–55% of the cytoplasm [19]. Considering the complex maturation states and classifications of mast cells, immunostaining is utilized as an index for mast cell tryptase and c-Kit, and ultrasonic examinations are also under evaluation [20]. Based on MC-specific proteases of chymase, tryptase, or carboxypeptidase A(MC-CPA) type, mast cells can be classified into MCT and MCTC in human beings [21,22] and MMC as well as CTMC in mice [23,24]. MCT is responsible for tryptases α and β(Ⅰ, Ⅱ, Ⅲ) and MCTC is also responsible for chymases CMA1 and MC-PCA. In mice, MMC is related to mMCP-1 and mMCP-2, and CTMC is responsible for mPCP-4, mPCP-5, mPCP-6, mPCP-7, and mPCP-9. Moreover, both MCT and MCTC are found in the mucosa of the GI and lung, whereas MCs are also identified in the skin and lymph nodes [25].

3. Mast Cells in IBD: Initiating Immunity and Maintaining Epithelial Barrier

3.1. Interactions between MCs and Cytokines: Initiating Immunity

MCs interact with nearly all immune cells and play vital roles in pathphysiology [26,27]. In times of inflammation, stem-cell factor (SCF), also known as the ligand for the receptor c-Kit (CD117), is considered the paramount survival and developmental factor for MCs [28], and other ligands, such as CXC chemokine receptor 2 (CXCR2) and cytokines, are also involved in MC maturation [29]. The chemokine (C-C motif) receptor 2 (CCR2)/chemokine (C-C motif) ligand 2 (CCL2) axis is implicated in MC recruitment in several models, including abdominal aortic aneurysm lesions [30] and increased in the gastric cancer cell line BGC-823 via the SCF/c-Kit signaling pathway activated by PI3K-Akt [31]. Exogenous intraperitoneal injection of IL-3 into human MCs during development could also result in mastocytosis [32].
MC and MC-derived granules remain at a low level to regulate the balance of water and electrolytes in healthy settings but are elevated in tissue inflammation, resulting in a cascade of immunological responses both in the gut and throughout the body [33,34]. Mas-related GPCR-X2 (MRGPRX2, mouse ortholog, MrgprB2), a novel human G protein-coupled receptor (GPCR) specifically expressed after IgE-mediated mast cell activation, promotes bacterial clearance and mucosal healing [35].
Elevated numbers of MCs are associated with diarrhea in the IBD [36], and in the SAMP1/YitFcs (SAMP1) mice model of spontaneous ileitis, an increased number of MC and elevated levels of the degranulation marker, β-hexosaminidase enzyme, were associated with inhibition of an essential Cl−/HCO3− exchanger (SLC26A3, also known as “down-regulated in adenoma (DRA)) [37]. As mentioned above, MCs also contribute to intestinal barrier dysfunction in ischemia reperfusion damage by activating the LR4-NF-κB/TNF-α pathway [38], and ATP-P2X7 purinoceptor-mediated activation in MC activation is involved in GI inflammation [39].
Granules secreted from MCs play an essential role in regulating gut homeostasis. Tryptase proteins stimulate the differentiation of human colon fibroblasts (CCD-18Co fibroblasts) into myofibroblasts via the Protease-Activated Receptors-2 (PAR-2)/Akt/mTOR pathway, allowing them to release more ECM proteins [40].

3.2. Roles of MCs in Maintaining Epithelial Barrier

Derived from monocytes, mast cells are capable of phagocytosis and protect the GI against infection [6]. In the meantime, MCs are also responsible for the maintenance of tight junctions and cytoskeletal proteins, which are essential for the GI epithelial barrier. MiR-223, an exosome-mediated functional miRNA, is abundant in MC-derived exosomes [23,24] and inhibits claudin-8 (CLDN8) expression in intestinal epithelial cells (IECs) [41]. Apart from directly down-regulating the epithelial barrier proteins, MCs also facilitated antigen transportation across the epithelium via upregulation of CD23 [42]. In physiological conditions, MCs promote migration and morphology-shifting of IECs and contribute to epithelial barrier permeability via mcpt4 and normal crypt expression of CLDN3 [43]. Similar effects are witnessed in the duodenum and ileocecal, and the one in the duodenum coincides with its involvement in functional dyspepsia (FD) [44], while clear mechanisms in the ileocecal remain unknown [45].
In allergic responses, tryptase secreted by mast cells can suppress the production of ubiquitin E3 ligase A20 (A20) in the intestinal epithelial cell lines, disturb the fusion of antigen-carrying endosomes and lysosomes, and promote antigen transport across the epithelial barrier, all of which contribute to intestinal epithelial barrier dysfunction [46]. And IL-9-deficient mice fail to develop oral-originated intestinal allergy via IL-9-mediated anaphylaxis [47].
Induction of enterotoxigenic Escherichia coli K88 also elevated the concentration of MC proteases (MCPs) and carboxypeptidase A3 (CPA3) mRNA levels, both of which are known as MC activators, and resulted in intestinal epithelial dysfunction [48]. Bacteria and other allergens are known as MC activators via Toll-like receptors (TLRs) and the nucleotide-binding and oligomerization domain (NOD) [49,50]. Naïve MC line human MC-1(HMC-1) cells or monocyte cell line THP-1 cells are used as standard models for investigations, and studies have corroborated their roles in pro-inflammatory cytokine secretion via NF-κB [51]. In allergic diseases, MC activation via the adenosine A3 receptor in response to myenteric neurons is accompanied by vagal afferent and 5-HT signaling [52,53].

4. Roles of MCs in Defending against Infection

Interactions between MCs and gut bacteria and their metabolites are also worth mentioning, as bacterial peptidoglycan could result in the breakdown of intestinal tolerance via TLR and NOD-mediated MC activation [49]. And bacteria overgrowth is related to increased MCP-2 in mice’s small intestines [54]. These investigations establish the basis for drug development and treatment for both neuronal and immune diseases [55,56]. Bacteria, as well as their metabolites, could regulate MC activation and over-proliferation [57]. Meanwhile, MC activation by other immune cells initiated by bacteria via cytokines like IL-33 and Fc receptors is also a significant protective measure in the GI [58]. These controls are also mediated by IL-3, IL-5, and GM-CSF [59]. These interactions, on the other hand, provide prospective targets for clinical therapy and medication research, such as the utilization of metabolites by beneficial bacteria such as Lactobacillus paracasei [60]. MC activation plays protective roles in pathological conditions, providing crucial mucosal defense against Strongyloides venezuelensis [61] and facilitating worm expulsion [62]. And reduced MC responses to bacterial antigen stimulation in C57BL/6 mice were confirmed in recent studies [63]. Diabetic mice showed reduced IL-3 and MC number levels, which could be induced by insulin, are associated with decreased immunity [64]. Other mediators, such as IL-4, stem cell factor, and nerve growth factor, have proven to suppress MC apoptosis in the human intestine in times of infection [65]. These findings lay the foundation for the pathological involvement of MCs in the gut and provide directions for future investigations. IL-33, associated with IL-3, is responsible for parasitic helminth expulsion via ILC2-mediated IL-9 secretion, resulting in MC-driven intestinal anti-helminth immunity [66]. It could also attenuate MC apoptosis via B-cell lymphoma-X large (BCLXL) [67]. Similar effects were seen in response to allergens and inflammation, with the involvement of CXCL1 [68,69].
However, higher levels of MC also facilitate small bowel cancer in mice [70], accompanied by improved epithelial permeability in IL-9 transgenic mice [71]. The double-edged role of IL-9 indicates the significance of homeostatic balance in GI related to MCs, and a better understanding of the underlying mechanisms might lead to more effective therapy. Meanwhile, other potential pathways for MC differentiation in other organs are summarized in previous reviews and have an indicative meaning for their uses in the GI [72,73] (refer to Figure 1 for the roles of MCs in the GI).

5. Roles of Mast Cells in IBS via Neurotransmitters and Molecules

Apart from secreting cytokines [74], MCs can release neurotransmitters and interact with the gastrointestinal nervous system [75]. MCs have intimate connections with GI neurons, as the number of MCs rises in response to stress along with increased macromolecular flux and epithelial mitochondrial swelling [76]. The enhanced corticotropin-releasing hormone (CRH) produced by eosinophils via substance P (SP) interacting with neurokinin receptors 1 and 2 on subepithelial mast cells could account for typical neurological diseases in IBS [77]. CRH signaling is also responsible for MC initiation of the GI nervous system [78]. MC stimulation improved the excitability of isolectin B4 (IB4)-positive colonic neurons while suppressing A-type K+ current (I(A)) density and shifting the inactivation curves of I(A) and I(K) in the hyperpolarizing direction in neuron cells [79]. Apart from neuron activation, MCs could also reduce enteric neuron survival in culture [80].
Histamine derives from histidine decarboxylation during MC maturation and serves as the initiator for angiectasis and tissue edema in response to pro-inflammatory factors [81]. Furthermore, it is involved in inflammation-associated colon carcinogenesis, in part by allowing L. reuteri-mediated suppression of keratinocyte chemoattractant (KC), IL-22, IL-6, Tnf, and IL-1α gene expression in the colonic mucosa [82] (refer to Box 1 for current understandings of mast cells and GI cancer). Meanwhile, histamine down-regulates IL-12p70 and CXCL10 production in mDCs after TLR2 and TLR4 stimulation via the small Rho GTPase CdC42 and PAK1 pathway [83]. Histamine could be secreted from mast cells and GI bacteria, and targeting bacterial histamine could be used to treat visceral hyperalgesia in IBS patients with chronic abdominal pain [84]. Apart from roles in inflammation and anti-infection, histamine from mast cells is also a significant mediator in food allergies, as shown in precision-cut intestinal slices (PCIS) [85,86], and leads to visceral hypersensitivity (VHS) in IBS [87]. Botschuijver et al. reported that fungal-induced release of mast cell-derived histamine could activate histamine-1 receptors on sensory afferents and induce sensitization of the nociceptive transient reporter potential channel V1 (TRPV1)-ion channel, and drugs targeting TRPV1 can be potential drugs for alleviating abdorminal pain [88]. However, there are also researchers who consider the influences of histamine on GI inflammation to be mediated via histamine receptor 4(H4R) but the concrete pathways underlying them remain unclear [84].
Box 1 Controversial roles in colon cancer
Mast cell proliferation in colorectal cancer (CRC) is related to angiogenesis, the number of malignant lymph nodes spreading, and the prognosis. Both angiogenic factors, including VEGF-A, CXCL 8, and MMP-9, and lymphangiogenic factors, including VEGF-C and VEGF-D, can be stored in granules and secreted [89]. On the one hand, a lack of MC showed enhanced CD8+T cell infiltration related to tumor proliferation [90]. On the other hand, a higher density of perivascular mast cells was observed in adenomas [91]. Further investigations put forward different expression patterns of MCs in different phases and areas of colorectal carcinoma [91]. Based on these findings, we suggest that more investigations are required to control the number and activation of MCs in colorectal cancer. Their interactions with other cells and underlying mechanisms should also be evaluated to clarify the comprehensive roles of MCs in colorectal cancer [90].
Serotonin (5-HT) is also detected in MC granules, with an increase in patients with mastocytosis [92], and dopamine storage is corroborated in rodent MCs and increased throughout maturation from bone marrow precursors [93]. These discoveries have provided major ramifications for the understanding of the complexities underlying the mechanisms of MC function processes. 5-HT spontaneous release is markedly enhanced, which coincides with the number of MCs and the severity of abdominal pain [94]. Gao et al. reported that mucosal serotonin reuptake transporter expression in IBS is modulated by the gut microbiota via mast cell-Prostaglandin E2(PGE2) [95]. This is also accompanied by the activation of enteric neurons and is higher in cases of intestinal inflammation [47]. The amount of muscularis tryptase-positive MC is also positively associated with GI transit time (GITT) throughout the healing process [96]. Therefore, the roles of MCs in the immune and nervous systems should be taken together in evaluating their roles in disease progression and treatment development.
Chymotrypsin-like (chymase) is another kind of granule serine proteinase released by MCs and is analogous to trypsin-like (tryptase). However, their expression patterns differ from each other and vary among the species, disease models, and phases [97,98]. Mucosal MCs of the rat express predominantly chymases, in particular rat mast cell proteinase (rMCP-2, -3, -4), and the three members of the rMCP-8 subfamily (rMCP-8, -9, and -10). Rat connective tissue MCs, on the other hand, express two chymases, rMCP-1 and -5, and two tryptases, rMCP-6 and -7 [99]. Tryptase could cleave the bronchodilator VIP and decrease the nonadrenergic neural inhibitory influence mediated by VIP [100], whereas ancestral chymase reconstructed with the use of phylogenetic inference, total gene synthesis, and protein expression are responsible for converting angiotensin I to angiotensin II [101]. However, both chymase and tryptase are known as mast cell proteinases and regulate GI tight junctions and gut permeability [99]. Increased cleavage specificity of mouse mast cell proteinase-1 (mMCP-1), the major mucosal MC protease, is found in several parasite mouse models [102,103] and indicates the high substrate selectivity they have. MCs are also activated via the TLR4-NF-κB/TNF-α pathway in 3- and 7-day-old rats with small intestinal ischemia-reperfusion(I/R) injury [104], resulting in increased mast cell carboxypeptidase A (MC-CPA), which could degrade toxins and endothelin 1 (ET-1) [105]. Despite the research, more detailed and comprehensive investigations of these granules would provide novel insights into GI pathology and effective treatment for patients.
Previous research confirmed the intimate interactions between MCs and the nervous system, which are primarily accomplished through granules secreted by MCs and receptors on neurons (Table 1). This establishes the anatomical foundation for the involvement of MCs in GI diseases and clinical symptoms in the nervous system. IBS is characterized by neuroinflammation and irregular and recurring digestive problems resulting from non-pharmacological or pathological stimuli as well as emotional feelings. Biopsies from IBS patients revealed elevated CXCL11 levels in the duodenum along with enhanced mast cell infiltration, suggesting relations between MC and micro-inflammation in IBS while more concrete interactions remain unknown [106]. Meanwhile, research confirmed that the amount of MC is associated with morphological changes in neuron densities during nematode Nippostrongylus brasiliensis (Nb) infection in mice and could be one of the underlying mechanisms for MC and inflammation [107]. These effects are also corroborated by MC inhibition via antinociception of oxytocin through the Ca2+-NOS pathway [108], accompanied by down-regulation of CXCL8, CCL2, CCL3, and CCL4 in human intestinal MCs by Cinnamaldehyde (CA) [109]. Polydatin also attenuated food allergy in MC by lowering the Ca2+ channel [110], and IFN-α/β showed similar effects, inhibiting intestinal hypersensitivity through MC stabilization [111]. More investigations on roles of MCs on GI diseases are summarized in Table 2 and detailed information on the mechanisms remains to be elucidate.
Based on the studies above, we infer that typical symptoms, including visceral hypersensitivity, are prevalent in IBS and are associated with mast cell overactivity and over-proliferation. Signals from neurons and immune cells both stimulate aberrant activities and provide novel avenues for treatment techniques and drug development via neurotransmitters and cytokines. Moreover, the majority of these factors could initiate various inflammatory pathways and lead to broader immune responses that are difficult to manage, and more precise regulation of molecules in key pathways is required.
Box 2 Interactions between MCs and viruses
Apart from bacterial infection, GI is also exposed to virus proliferation [138]. Some viruses can directly infect MCs and activate them [139]. Research found that MCs might enhance NK cell activities and upregulate the CD69 molecule and cytotoxicity-related genes in response to virus-infected mast cells, demonstrating increased cytotoxic activity in response to virus-infected mast cells. Also, mast cells express numerous pattern recognition receptors (PRRs) and secrete inflammatory mediators that have historically been engaged in the antiviral response in the gut. MC interactions with viruses and pathogen products, on the other hand, are complicated and can have adverse and beneficial consequences. MCs can limit viral infection by releasing antiviral mediators and interacting with γδ T cells [140]. However, the detailed mechanisms between MCs and viruses in the gut are not yet completely clarified.
In IBS and GI infection, the number of MCs increased [141] in accordance with the number of neurons [142]. Morphological alterations in IBS [143] and their interactions with the brain have also been put forward as part of the gut–brain axis [144]. However, despite the higher level of mast cells in the gut–brain axis observed in IBS [145], no evidence supports their roles in the gut–brain axis [116]. Mast cells could secrete nerve growth factor (NGF) and contribute to IBS [146]. However, in the rat IBS model, NGF is localized more in the mucosal enteric glial cells (EGCs) but not in the mucosa mast cells. And glial processes in the submucosa of the colon showed bulbous swelling of terminals that overlapped with neurons, known as glial hyperplasia [116]. An increased number of MCs is also seen in several psychological diseases, including neonatal maternal deprivation and stress, and indicates the similarities underlying them [147,148]. In IBS patients, enhancing mesenteric nerve firing and mobilization of Ca2+ in dorsal root ganglia neurons are related to the activation of MC accompanied by histamine release and higher neuronal sensitivity to capsaicin [149]. Moreover, B0AT1, Na+-dependent glutamine co-transporters, in villus cells, and SN2 in crypt cells are also regulated by MCs, decreasing co-transporter numbers in villus and enhancing affinity for glutamine in crypt cells [116]. SHIP, a hematopoietic-specific lipid phosphatase, can dephosphorylate PI3K-generated PI(3,4,5)-trisphosphate and suppress the activation of MC, alleviating Crohn’s disease in the GI [150]. And substance P and other eicosanoids secreted by MCs could lead to neuron activation [151]. Based on the summaries above, addressing an increased number of MCs might provide a novel aspect in the prevention and treatment of Crohn’s disease in future research.

6. Conclusions and Future Perspectives

MCs encompass different kinds of bioactive molecules that are generated upon activation and participate in various biological functions. They could interact with cells of both immunological and nervous system cells, as well as microbes in the GI. These processes are critical for GI homeostasis, and MC malfunction can result in severe disorders impairing life quality (refer to Figure 2 for detailed information).
In this review, we provided a detailed illustration of MC properties and classifications, as well as their involvement in maintaining GI barrier functions. We further analyzed their interactions with immune cells and neurons and especially highlighted MCs’ prospective applications in therapeutic development. These provide directions for future investigations and have crucial roles in both clinical and pathological research.

Author Contributions

Y.G. and B.W. analyzed the reference and wrote the manuscript. Y.G., B.W. and R.H. polished the images. C.H., S.Z., X.L. and S.X. analyzed the data. H.G., S.Z. and J.X. revised the manuscript. All authors have read and agreed to the published version of the manuscript.

Funding

This work was supported by the National Natural Science Foundation of China Grant (No. 82174056 JD Xu).

Institutional Review Board Statement

Not applicable.

Informed Consent Statement

Not applicable.

Data Availability Statement

All data available.

Conflicts of Interest

The authors declare no conflict of interest.

Abbreviations

BCLXLB-cell lymphoma-X large
CAcinnamaldehyde
CP carboxypeptidase
C-C motifchemokine
CCL2chemokine ligand 2
CCR2chemokine receptor 2
CD117c-Kit
chymaseChymotrypsin-like
CLDN8claudin-8
COXcyclooxygenase
CPA3carboxypeptidase A3
CRCcolorectal cancer
CRHcorticotrophin-releasing hormone
CTMCconnective tissue mast cells
CXCR2CXC chemokine receptor 2
ET-1endothelin 1
FDfunctional dyspepsia
FOS fructo-oligosaccharides
FD functional dyspHmm
GIgastrointestinal
GPCRG protein-coupled receptor
H4Rhistamine receptor 4
HMC-1human mast cell-1
HMCs-1human mast cells-1
I/Rischemia-reperfusion
IBDinflammatory bowel disease
IBSirritable bowel syndrome
IECsintestinal epithelial cells
IECs intestinal epithelial cells
IPC ischemic preconditioning
IB4 isolectin B4
KCkeratinocyte chemoattractant
Mφmacrophage
MCPmast cell proteases
MMCmucosal mast cells
MRGPRX2mMas-related GPCR-X2
Nbnippostrongylus brasiliensis
NGFnerve growth factor
NODnucleotide-binding and oligomerization domain
NSAIDsnon-steroidal anti-inflammatory drugs
PAR-2protease-activated receptors-2
PCISprecision cut intestinal slices
PGsprostaglandins
SCFstem-cell factor
TLRToll-like receptors
TRPV1transient reporter. potential channel V1
VHSvisceral hypersensitivity
VIPvasoactive intestinal peptide

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Figure 1. Underlying mechanisms of MC in the GI tract. MCs are pivotal regulators of GI via interactions with immunological and neurological system cells. Triggers could be signals from both parasites (A) and antigens presented in other immune cells by recognizing factors like TLRs and CDs (C). Both epithelial cells and enteric neurons are involved in this regulation, primarily achieved by granule secretion (B) via key molecules including CXCL3, IL-3, and IL-33, which further stimulates MC proliferation, culminating in cascades of host reactions (D). In both physiological (E) and IBS (F), MCs are significant regulators of the enteric nervous system, and their number increased in IBS. However, detailed understandings of them remain elusive.
Figure 1. Underlying mechanisms of MC in the GI tract. MCs are pivotal regulators of GI via interactions with immunological and neurological system cells. Triggers could be signals from both parasites (A) and antigens presented in other immune cells by recognizing factors like TLRs and CDs (C). Both epithelial cells and enteric neurons are involved in this regulation, primarily achieved by granule secretion (B) via key molecules including CXCL3, IL-3, and IL-33, which further stimulates MC proliferation, culminating in cascades of host reactions (D). In both physiological (E) and IBS (F), MCs are significant regulators of the enteric nervous system, and their number increased in IBS. However, detailed understandings of them remain elusive.
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Figure 2. Schematic summary of the MC function. MCs are multifunctional immune cells that release multi-potent active molecules to regulate many physiological functions and immunological responses. They have been found to impact vasodilation, vascular homeostasis, and angiogenesis and possess close interactions with dendritic cells, macrophages, T cells, B cells, fibroblasts, eosinophils, endothelial cells, and epithelial cells.
Figure 2. Schematic summary of the MC function. MCs are multifunctional immune cells that release multi-potent active molecules to regulate many physiological functions and immunological responses. They have been found to impact vasodilation, vascular homeostasis, and angiogenesis and possess close interactions with dendritic cells, macrophages, T cells, B cells, fibroblasts, eosinophils, endothelial cells, and epithelial cells.
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Table 1. Summary of the functions and mechanisms of mast cells.
Table 1. Summary of the functions and mechanisms of mast cells.
ModelFindingsConclusionsPossible SenseRefs
Mice with lactose or FOSIncreased MCs in colonic mucosaLactose or FOS could increase MCs in colonic mucosa and affect the GI barrier functionsRegulators of MCs[112]
Functional dyspepsia (FD)Increased MCs in colonic mucosaEosinophils and MCs are relative to FD Effective regulators of FD MCs remain unclear[95]
Exosomes isolated from HMCs-1or CaCO2 of IECsInhibited expression of CLDN8, CD23, mcpt4, CLDN3, and A20 in IECs MC regulated GI barrier functions via regulating CLDN8, CD23, mcpt4, CLDN3 and A20Potential drugs targeting gut permeability[41]
HT29 Upregulated CD23 expression MCs modulate transport of CD23/IgE/antigen complex across intestinal epithelial barrierPromoting antigen transportation[42]
Adult male SD ratsMCs activated by substance P (SP)Improved the excitability of IB4+ colonic neurons but pressing IA and shifting the inactivation of IA and IK in the hyperpolarizing direction in neuron cellsRegulation of ion transportation by MCs remains unclear[79]
Preclinical or IBS patientsMCs and bacteria secrete histaminevisceral hypersensitivity (VHS)Histamine is a marker and target for regulating VHS[113]
Polyposis-prone miceMCs secrete histamine during maturationInvolved in Inflammation-associated colon carcinogenesis/
C57Bl/6 miceMCs secrete serotonin with mastocytosisAssociated with abdominal painSerotonin is a target for the treatment of abdominal pain and diarrhea[114]
Male rabbits with intragastric inoculation of Eimeria magna oocytesB0AT1 and SN2 in crypts are regulated by MCsMCs regulated gut permeability B0AT1 and SN2 as potential targets in MCs related to IBS[115]
WKY and IBS rat model by balloon catheter insertionMCs could secrete NGF but are probably not directly associated with IBS Expression of NGF is not in the same area of MCsA more precise relationship between MC and enteric neurons is required[116]
SD ratsCPA is secreted by MCs in I/R injuryMC limit toxins and ET-1 in I/R injuryIPC protected against I/R injury via the MC degranulation-mediated release of MC-CPA[104]
Specimens from patientsEnhanced level of CXCL11 in IBSPositive correlation between the MCs number of duodenal and ileal IELs in diarrheaCXCL11 as potential target and marker for IBS[106]
IEC lines Lowering A20 production Tryptase suppressed A20 in the IEC lines and lowered barrier dysfunctionTreatment targeting allergens[46]
Table 2. Key molecules related to MCs and their roles in typical diseases.
Table 2. Key molecules related to MCs and their roles in typical diseases.
DiseasesKey MoleculesMast Cell AlterationsTypical SymptomsRefs
IBSAdvanced glycation end products (AGEs)Number increasedColonic mucus barrier dysregulation in mice
5-HT and SERTMain sourcesDiarrhea and visceral hypersensitivity
5-HT signalingNumber increasedStress parameters[55]
Histamine and HR4MC activationVisceral hyperalgesia[84]
Serine ProteaseMC infiltrationFunctional dyspepsia (FD)[117]
EstrogenMC infiltrationStress-worsened intestinal alterations[118,119]
Nr4a3Promoted MC activityStress-induced visceral hyperalgesia in mice[120]
Active VIP and VIP receptors (VPAC1/VPAC2)Increased MC and VPAC1+ MC numbers and decreased VIP+ MCDetrimental consequences to colonic permeability[121]
AcetylcholineMast cell overactivationVisceral hypersensitivity (VH)[122]
Hereditary α-tryptasemia (HαT)Increased MC numberIEC pyroptosis[123]
5-HTIncreased MC activationIntestinal dysfunction and depression-like behaviors[124]
IL-1β, IL-6, PAR-2, and mast cell tryptase Visceral hypersensitivity[125]
TLR4Enhanced MCs activationVisceral hypersensitivity and barrier loss[126,127]
GI cancerTryptase release after c-Kit receptor activationMast cell activationIncreased number of metastatic lymph nodes[128]
Inflammatory responsesMC densityBenign cancer[129]
Angiogenesis and carcinoma progressionMC densityPatient malignancy[130]
c-Kit receptor-related pathwayMC numberEarly time intestinal tumor[131]
Colitis Ki-67 and β-catenin proteinMC activationGastrointestinal tumorigenesis[132]
MRGPRX2-mediatedMC degranulationMC degranulation and activation modules[34,133]
Not mentionedMC counts and degranulationGastrointestinal motility[134]
Mannose receptor (MR)Mφs/MC distributionMφs/MC distribution[96]
Kit-mediatedMC activationExperimental colitis[135]
P2X7 purinoceptorsMC activationIntestinal inflammation[39]
free-Ca2+ and GTPγSMC activationSecretory responses[136]
ADMast cell-glia axis and a Fyn kinaseMCs activationAggravated AD pathology[137]
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Guo, Y.; Wang, B.; Gao, H.; He, C.; Xin, S.; Hua, R.; Liu, X.; Zhang, S.; Xu, J. Insights into the Characteristics and Functions of Mast Cells in the Gut. Gastroenterol. Insights 2023, 14, 637-652. https://doi.org/10.3390/gastroent14040043

AMA Style

Guo Y, Wang B, Gao H, He C, Xin S, Hua R, Liu X, Zhang S, Xu J. Insights into the Characteristics and Functions of Mast Cells in the Gut. Gastroenterology Insights. 2023; 14(4):637-652. https://doi.org/10.3390/gastroent14040043

Chicago/Turabian Style

Guo, Yuexin, Boya Wang, Han Gao, Chengwei He, Shuzi Xin, Rongxuan Hua, Xiaohui Liu, Sitian Zhang, and Jingdong Xu. 2023. "Insights into the Characteristics and Functions of Mast Cells in the Gut" Gastroenterology Insights 14, no. 4: 637-652. https://doi.org/10.3390/gastroent14040043

APA Style

Guo, Y., Wang, B., Gao, H., He, C., Xin, S., Hua, R., Liu, X., Zhang, S., & Xu, J. (2023). Insights into the Characteristics and Functions of Mast Cells in the Gut. Gastroenterology Insights, 14(4), 637-652. https://doi.org/10.3390/gastroent14040043

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