Mast cell-mediated microRNA functioning in immune regulation and disease pathophysiology

Abstract

Upon stimulation and activation, mast cells (MCs) release soluble mediators, including histamine, proteases, and cytokines. These mediators are often stored within cytoplasmic granules in MCs and may be released in a granulated form. The secretion of cytokines and chemokines occurs within hours following activation, with the potential to result in chronic inflammation. In addition to their role in allergic inflammation, MCs are components of the tumor microenvironment (TME). MicroRNAs (miRNAs) are small RNA molecules that do not encode proteins, but regulate post-transcriptional gene expression by binding to the 3’ non-coding regions of mRNAs. This plays a crucial role in the function of MC, including the key processes of MC proliferation, maturation, apoptosis, and activation. It has been demonstrated that miRNAs are also present in extracellular vesicles (EVs) secreted by MCs. EVs derived from MCs mediate intercellular communication by carrying miRNAs, affecting various diseases including allergic diseases, intestinal disorders, neuroinflammation, and tumors. These findings provide important insights into the therapeutic mechanisms and targets of miRNAs in MCs that affect diseases. This review discusses the relevance of miRNA production by MCs in regulating their own activity and the effect of miRNAs putatively produced by other cells in the control of MC activity and their participation in selected pathologies.

Introduction

Mast cells (MCs) are bone marrow-derived cells that develop from multipotent hematopoietic progenitors, migrate to different organs, and respond to cytokines and stem cell factors localized in these tissues [1]. These cells are primarily found in areas proximal to the external environment, including the respiratory and gastrointestinal tracts and the skin [2]. MCs act as sentinels, detecting threats and initiating inflammatory responses when stimulated. They are long-lived cells that can re-enter the cell cycle and proliferate upon stimulation [2]. MCs can secrete a broad panel of both preformed and de novo synthesized mediators, including cytokines, chemokines, and histamine, which mediate immunomodulatory functions. Furthermore, the strength and nature of MC responses depend on the type and intensity of the activating signal, whether it is cross-linking of the high-affinity immunoglobulin E (IgE) receptor (FcεRI), lipopolysaccharide (LPS) stimulation, or histamine receptor triggering [3, 4]. They also generate newly synthesized potent inflammatory mediators such as leukotriene C4, prostaglandin D2, and cytokines. Once released, these bioactive mediators initiate inflammatory responses within the mucosa that can potentially exacerbate conditions such as allergies and asthma.

MicroRNAs (miRNAs) are small, non-coding RNA molecules, typically ranging from 19 to 25 nucleotides in length, that function in post-transcriptional regulation and facilitate the silencing of gene expression through RNA interference [5, 6]. As such, they are able to regulate various cellular processes, such as differentiation, proliferation, survival, apoptosis, stress response, effector function, and resolution of immune responses [7, 8]. MiRNAs usually belong to families consisting of evolutionarily related members that partially share sequences and targets [9]. In the human genome, there are approximately 239 different miRNA families, which together express more than 2000 different mature miRNAs. A particular miRNA can have hundreds of target genes, and a single gene is usually targeted by multiple miRNAs. Thereby, miRNAs are thought to affect the expression of approximately 30% of genes [5]. MiRNAs are widely recognized as modulators of many aspects of the immune system. Unique miRNA expression profiles are found in the cells of the adaptive and innate immune systems, regulating lineage commitment, proliferation, effector functions, and differentiation in normal and disease conditions [10, 11].

MiRNAs have also been reported to be present in extracellular vesicles (EVs) secreted by cells [12, 13]. EVs are vesicles of endocytic origin released by many cells. These vesicles can carry biological macromolecules, including proteins, lipids, and miRNAs and mediate communication between cells, facilitating processes such as antigen presentation [14–18]. Studies have shown that EVs released from MCs contain miRNAs, which can be transferred from MCs to recipient cells via EVs and affect the function and phenotype of the recipient cells [19, 20]. EV-mediated miRNA transfer has been implicated in inflammatory diseases and allergic diseases [21–23], inflammatory responses [17], systemic mastocytosis [24], and tumor metastasis [25, 26].

In this review, we focus on the mechanisms by which miRNAs regulate MC function and their potential applications in MC-related diseases. This review provides new insights into the role of miRNAs in regulating MC function, and suggests future research directions and potential clinical applications are proposed.

Characteristics and functions of MCs

MCs are granular immune cells derived from hematopoietic stem cells around the microvessels in connective and mucosal tissues [27]. In humans, MCs are classified into two primary subsets based on their granule composition: tryptase-rich mast cells in mucosal tissues (MCT) and tryptase- and chymase-rich mast cells in connective tissues (MCTC). Interactions between resident tissues and MCs contribute to MCs' phenotypic and functional heterogeneity in early and adult life. For example, bone marrow-derived mast cells (BMMCs), fetal skin MCs, and fetal liver. MCs are all classified as connective tissue MCs with comparable morphology, but display unique features in individual transcriptomes with different granule contents, indicating differences in MC development depending on the tissue of origin [28]. MCs are best known as master effector cells in allergic responses and anaphylaxis, but although harmful effects are the best-characterized consequences of MC activation, these cells also have established protective roles, for example, in toxin degradation and resistance to bacteria and parasites [29]. In the context of inflammation, MCs can enhance the overall response, as in allergic diseases, but depending on the environment they can also act as suppressor cells [30]. Interestingly, MCs are protective during experimental oxazolone-induced dermatitis, with a mechanism requiring MC-derived IL-2 to maintain the appropriate ratio of activated T cells to regulatory T cells (Tregs) at the site of inflammation, highlighting the importance of the crosstalk between MCs and other immune cell types [31]. MCs also release a variety of VEGF growth factors, which are used to promote angiogenesis [32]. MC interactions with microorganisms may be a bidirectional response, with interactions with the microbiota affecting MC distribution in the lung. Studies show that wild-caught mice have high numbers of MCs in the lung parenchyma compared to conventional pathogen-free laboratory animals. Remarkably, when laboratory mice are bred in conditions that mimic the wild environment, they exhibit increased numbers of MCs in the lungs [33]. Several studies have hypothesized a role for MCs in tumor development and progression [34] and correlated their infiltration with a poor prognosis in gastrointestinal tumors [35–38]. Thus, MCs have been implicated in numerous pathophysiological processes, including tissue reconstruction, angiogenesis, autoimmune damage, and tumorigenesis [39].

MiRNAs regulate the biological functions of MCs

Recent studies have emphasized the significance of miRNAs in regulating various aspects of MC biology. miRNAs play crucial roles in controlling MC differentiation, proliferation, survival, apoptosis, stress response, effector function, and resolution of immune responses [40–44]. These processes are essential under both physiological and pathological conditions, highlighting the importance of miRNA-mediated regulation in MC biology. Figure 1 provides further details.

Fig. 1.

miRNAs regulate the biological functions of MCs

The red arrow indicates overexpression, the blue arrow indicates decreased expression. Different miRNAs regulate MC differentiation, proliferation, survival, apoptosis, degranulation, etc. Figure created with Figdraw.com

Recent studies have shown that several miRNAs are involved in the regulation of the MC cycle, proliferation, and maturation. In BMMCs, miR-221–222 was upregulated upon cell activation under resting or stimulated conditions, and its overexpression dampened cell proliferation without affecting differentiation. Furthermore, miR-221–222 could be regulators of the cell cycle in a cell type and activation dependent manner [42]. Lee et al. showed that decreased expression of both miR-539 and miR-381 in association with c-Kit signaling promotes the expression of the transcription factor Mitf, leading to MC proliferation [43]. The interaction between KIT and stem cell factor (SCF) seems to play an essential role in the development of mastocytosis. Activating somatic mutations in c-kit, which encodes KIT, have been detected in the bone marrow, skin and peripheral blood cells of patients with mastocytosis [45].The receptor tyrosine kinase KIT and its ligand SCF are essential for human MCs’ survival and proliferation. Activation of KIT and its early signaling cascades stimulate the secretion of exosome-like EVs in a regulated manner, which may have implications for KIT-driven functions [46]. These studies demonstrate the role of specific miRNAs in controlling MC proliferation and maturation and provide potential targets for modulating MC functions. When miR-126 is downregulated during MC maturation, Sprouty-related Ena/VASP homology-1 domain-containing protein (Spred1) levels increase, and MC numbers and cytokine production are affected [44]. Conversely, conditional knockout of Spred1 leads to increased MC numbers and cytokine production after activation [44]. Overexpression of miR-223 promotes MC apoptosis by targeting the insulin-like growth factor-1 receptor (IGF-1R) [47]. MiR-146a also acts as a pro-apoptotic factor in MCs, as its overexpression negatively regulates nuclear factor kappa-B (NF-κB) and increases cell death [48]. These findings suggest that miRNAs play a role in regulating MC survival and apoptosis, which may have implications in MC-related diseases [49, 50].

Specific miRNAs have also been reported to be involved in MC differentiation and activation. After activation, BMMCs showed an increase in 13 miRNAs and a decrease in seven miRNAs [51]. Similarly, another study demonstrated that seven miRNAs were upregulated and ten were downregulated in activated BMMCs, with miR-21a and miR-3113 showing the most significant changes. The potential target genes of these candidate miRNAs were enriched in FcεRI signaling, stimulus–response, and exocytosis pathways [52].

Yang et al. used miRNA arrays to profile miRNA expression in BMMCs [53]. They identified 86 unique miRNAs that showed significant changes in expression, of which 45 were upregulated and 41 were downregulated. Functional enrichment analysis revealed a correlation between these miRNAs and processes such as cell cycle, growth, apoptosis, and activation. In addition, seven miRNAs were found to correlate with the expression of c-kit and FcεRIα, while 18 miRNAs were associated with key transcription factors involved in MC differentiation (Mitf, GATA1, and c/EBPa).

MCs are also regulated by miRNAs in terms of degranulation and migration. In addition to affecting the cell cycle of MCs, miR-221 promotes IgE-mediated degranulation and cytokine production through the PI3K/Akt/PLCγ/Ca²⁺ pathway, increasing cell adhesion and decreasing cell migration [54, 55]. Let-7i suppressed Exco8, which is associated with MC degranulation, thereby inhibiting MC degranulation [51]. In addition, the pathway inhibitor, propofol has been shown to attenuate MC degranulation [56]. Reduced miR-223 promotes degranulation via the PI3K/Akt pathway by targeting the IGF-1R in MCs [57]; miR-223 also reduces IL-6 secretion in MCs by inhibiting this pathway [58]. Overexpression of miR-142-3p can promote FcεRI-mediated degranulation in MCs by counteracting the silencing effect of Dicer [59]. These studies highlight the complex role of miRNAs in regulating MC activation and degranulation, with some miRNAs promoting these processes and others inhibiting these processes. Understanding the specific pathways and targets of these miRNAs may provide opportunities to modulate MC function in various disease states.

In chronic spontaneous urticaria, miRNA-101-5p has been shown to enhance platelet-activating factor (PAF)-induced MC degranulation, whereas heat shock protein 10 (HSP10) inhibits this process [60]. MiR-126 enhances IgE-mediated MC degranulation via the PI3K/Akt pathway by promoting Ca²⁺ influx [61]. Overexpression of miR-375 in oesophageal epithelium inhibits MC activation [62]. miR-155 positively regulates prostaglandin and cytokine pathways in MCs by targeting cyclooxygenase 2 (COX-2) expression and inhibiting Akt phosphorylation [63]. IL-10 induces miR-155 expression in MCs, which in turn increases protease and cytokine production by inhibiting the cytokine signaling inhibitor suppressor of cytokine signaling-1 (SOCS1) [64]. MiR-20a suppresses tumor necrosis factor-alpha (TNF-α), interleukin-1 beta (IL-1β), and interferon-gamma (IFN-γ) expression in human MCs while promoting IL-10 expression. In addition, miR-20a also targets histone deacetylase 4 (HDAC4), which promotes epigenetic regulation of IL-10 expression [65]. These findings suggest that miRNAs play a role in modulating the balance between pro-inflammatory and anti-inflammatory cytokines in MCs, which may have implications in various inflammatory diseases.

MCs are also regulated by miRNAs during development. Yang et al. identified 86 miRNAs characterized by a fivefold differential expression during BMMC development. Among the miRNAs selected for validation, miR-223 was found to play a central role in myeloid cell development [53]. Other miRNAs have also been implicated in to cell development, inflammation, and disease.

Recent studies show that Toll-like receptor 8(TLR8) gene modulation using miRNA via a salmonella vector has a dual protective effect against atopic dermatitis (AD). TLR8 downregulation reduced macrophage-derived chemokine levels in activated human MCs. Investigation of the modest regulation of TLR signaling by miRNAs and the synergistic effect with the salmonella vector may lead to the identification of promising targets for drug discovery against this chronic, recalcitrant inflammatory skin disease [66].

Effects of miRNAs on MCs in disease

Allergic diseases

MiRNAs play a dual role in the regulation of MC activation and function by acting either as inducers or suppressors, depending on the specific context, the origin of MCs, and inflammatory disease. By targeting different molecular targets involved in MC activation pathways, miRNAs can influence the activation status of MCs and affect their functional responses under allergic conditions (Table 1).

Table 1.

Functions of miRNAs in MCs

MiRNA	origin of miRNAs	Trigger	MiRNA effects on MCs	Target	Ref
miR-155	BMMCs BMMCs	FcεRI IL-10	Increases degranulation and cytokine release Increases production of cytokines	PI3K SOCS1	[67] [64]
miR-20a-5p	HMC-1 cells	PMA/Ion	Inhibits production of pro-inflammatory cytokines	HDAC4	[65]
miR-210	HMC-1 cells	IgE	Plays a role in activation	–	[68]
miR-221-3p	P815 MCs	–	Increases IL-4 secretion	PTEN, p38, and NF-κB pathways	[69]
miR-143	HMC-1 cells	–	Reduces activation	IL-13Rα1	[70]
miR-302e	HMC-1 cells	–	Exhibits anti-inflammatory effect	NF-κB	[71]
miR-103a-3p	HMC-1 cells	Fcε RI	Increases IL-5 production	–	[72]
miR-135a	AR mice T cells	–	Suppress the infiltration MCs into the nasal mucosa	GATA-3	[73]
miR-152-3p	RBL-2H3 cells	Metformin	Inhibits MC activation and airway resistance	IR/IGF-1R	[74]
miR-194	HMC-1 cells	–	Decreases inflammatory response and HDMEC permeability	THBS1 and TGF-β/SMAD pathway	[75]

MiR-155 is an important microRNA that plays a central role in the regulation of MC activation and immune responses. It affects various components of the PI3K pathway, which is involved in MC activation via the FcεRI receptor. Mice lacking miR-155 showed increased allergic responses [67]. These studies highlight the importance of miR-155 in modulating MC function and inflammatory responses in allergic diseases. The effects of IL-10 are dependent on Stat3 activation, which induces miR-155 expression with a consequent loss of suppressor of cytokine signaling-1. IL-10 also enhances anaphylaxis in miR-155-deficient mice.[64]. This suggests that the role of miR-155 in MC regulation is complex and may depend on the specific cytokine milieu and signaling pathways involved.

Downregulation of miR-20a in response to MC activation by phorbol 12-myristate 13-acetate (PMA) and ionomycin (A23187) has been associated with significant effects on the production of inflammatory cytokines and the regulation of immune responses. In particular, the overexpression of miR-20a in activated MCs has been shown to inhibit the production of pro-inflammatory cytokines, including TNF-α, IL-1β, and IFN-γ, while promoting the production of the anti-inflammatory cytokine IL-10. HDAC4 is a potential target of miR-20a. By targeting and suppressing HDAC4 expression, miR-20a contributes to the epigenetic regulation of IL-10 expression. This regulatory mechanism involving miR-20a and HDAC4 highlights the intricate interplay between miRNAs, epigenetic modifications, and cytokine production in MCs [65].

In asthma, several miRNAs have been shown to play a role in modulating MC activation and allergic inflammation. For example, miRNA-210 is upregulated in MCs following IgE sensitization in individuals with asthma [68]. Another miRNA, miR-221-3p, is observed at higher levels in patients with asthma. This miRNA targets phosphatase and tensin homolog (PTEN) and activates both the p38 and NF-κB pathways, leading to increased IL-4 secretion in MCs [69]. These findings suggest that miR-210 and miR-221-3p contribute to the pathogenesis of asthma by promoting MC activation and Th2 cytokine production. Conversely, miR-143 reduces MC activation and subsequent allergic responses by targeting IL-13Rα1 [70]. MiR-302e exerts an anti-inflammatory effect in allergic conditions by inhibiting NF-κB activation [71]. These miRNAs may have potential as therapeutic targets to modulate MC functions in asthma. Another important miRNA is miR-103a-3p, which was observed in EVs of FcεRI-aggregated human MCs. It increased IL-5 production in group 2 innate lymphoid cells, exacerbating eosinophilic allergic inflammation [72]. This suggests that miR-103a-3p contributes to the crosstalk between MCs and innate lymphoid cells in allergic diseases. MiR-135a is another miRNA that plays a role in modulating allergic inflammation in MCs. It targets GATA-3, a transcription factor involved in the regulation of Th2 cell differentiation and cytokine production. By targeting GATA-3, miR-135a can potentially downregulate Th2 cytokine production and mitigate allergic inflammation [73]. Studies have shown that exosomal miRNAs influence the pathogenesis of asthma by modulating MC activation and airway inflammation. For example, miR-21 released from MC-derived EVs can exacerbate asthma by increasing airway inflammation and oxidative stress, which are key features of asthma pathogenesis [57]. These studies suggest that exosomal miRNAs play a role in the communication between MCs and other cell types in the airways.

In a study by Dan, metformin, a medication commonly used to treat of type 2 diabetes, inhibited MC activation and airway resistance in a combined model of type 2 diabetes and asthma. The mechanism involved weakening the binding affinity between miR-152-3p and DNMT1, leading to downregulation of the insulin receptor/insulin-like growth factor-1 receptor (IR/IGF-1R). This downregulation contributed to the suppression of MC activation and improved airway resistance in this model [74]. This study suggests that metformin may have potential as a therapeutic agent for the treatment of asthma in patients with type 2 diabetes and that miR-152-3p may be a key player in this process.

MiR-194 plays a critical role in attenuating MC inflammation and in reducing the permeability of human dermal microvascular endothelial cells in chronic idiopathic urticaria. This is achieved by negatively regulating thrombospondin 1 (THBS1) and inhibiting the TGF-β/SMAD pathway. By targeting THBS1 and modulating the TGF-β/SMAD pathway, miR-194 can temper MC-mediated inflammation and reduce endothelial cell permeability. This, in turn, mitigates the symptoms of chronic idiopathic urticaria [75]. In an ACD95 mouse model, miR-21 was shown to protect against 2,4-dinitrofluorobenzene-induced allergic contact dermatitis. This was achieved by inhibiting the p38 pathway, which subsequently suppressed MC degranulation. By downregulating the p38 pathway, miR-21 can mitigate allergic responses and reduce the severity of dermatitis in this model [76].

These findings highlight the role of miRNAs in modulating MC activation and inflammation under various allergic conditions, including allergic contact dermatitis and chronic idiopathic urticaria. Further research is required to better understand the underlying mechanisms and explore the therapeutic potential of targeting these miRNAs in the management of allergic diseases.

Tumors

Tumor initiation and progression are dynamic processes regulated by cancer cells and associated with changes in the tumor microenvironment (TME) [77]. MCs play a significant role in this process by producing, storing, and releasing the chemical mediators. This triggers a series of cellular and molecular interactions that induce the remodeling of the TME and mediate a more aggressive phenotype [34, 78, 79]. MCs can also recruit immune cells capable of fighting tumors. Thus, MCs may play an important role in the first phase of cancer immunoediting, which is elimination (also known as immunosurveillance) [80]. Understanding the communication between MCs and other cells within the TME, including the transfer of miRNAs through EVs, is crucial for developing targeted therapeutic strategies to disrupt these interactions and potentially hinder tumor progression (Table 2).

Table 2.

Relationships between MiRNA and Tumor diseases

MiRNA	origin of miRNA	Tumor diseases	Ref
miR-9	Human mast cell	Salivary gland tumors	[81]
miR-106b-5p	TCGA database	Oesophageal squamous cell carcinoma	[82]
miR-32 miR-218/−181 miRNA-26a/−26b miR-1405p miR-223-3p/ miR-125b-5p miR-182/183-5p	Human mast cell B16F1 mouse melanoma Cells COX-2 knockout mouse cell CT26 cells Transgenic male mice (K14-HPV16) Cholangiocarcinoma cells-EVs	Prostate cancer Tumor metastasis Tumorigenic and Metastatic Potential of Cancer Cells Tumor-induced MC autophagy HPV Cholangiocarcinoma	[83] [84] [85] [86] [87] [88]

Oral neoplasms

Some studies have provided insight into the role of miRNAs in the regulation of MC function and their potential involvement in the pathogenesis of MC-related diseases and oral tumors. In a study by Lee et al., the downregulation of miR-539 and miR-381 clusters has been shown to be associated with malignant MC proliferation. These miRNAs reduce the levels of MITF, a transcription factor essential for MC development and function, leading to a decreased colony-forming ability of MCs [43]. This suggests that the dysregulation of these miRNAs may contribute to the pathogenesis of MC-related diseases, including oral neoplasms. Poliana et al. [81] investigated the expression patterns of miRNAs associated with MC activation and angiogenesis in paraffin-embedded salivary gland tumors. Specifically, one study reported that miR-9 was significantly upregulated in tumors compared to normal glandular tissue. In contrast, miR-17, miR-132, miR-195, and miR-221 are significantly downregulated in the tumors. Mucinous epithelial-like carcinomas have a higher density of MCs, suggesting that salivary gland tumors typically have different miRNA expression profiles than normal glandular tissues. These findings provide insight into the potential role of MCs and their associated miRNAs in the pathogenesis of salivary gland tumors.

Gastrointestinal tract neoplasms

In a study by Peng, a characteristic miRNA-lncRNA regulatory pair, miR-106b-5p/KIAA0232, was identified in esophageal squamous cell carcinoma (ESCC). Integrating the TCGA database and GEO datasets, it was noted that the expression levels of miR-106b-5p and KIAA0232 were found to correlate negatively and positively, respectively, with the proportion of resting MCs [82].

Exosomal miRNAs derived from MCs have been implicated in regulating tumor progression in gastrointestinal cancers, such as hepatocellular carcinoma (HCC) and cholangiocarcinoma (CCA). For example, in HCC, MC-derived exosomal miR-490 suppressed tumor invasion and metastasis by inhibiting the EGFR/AKT/ERK1/2 signaling pathway [89]. In CCA, EV-transported miR-182/183-5p promotes cancer cell proliferation, invasion, and epithelial-mesenchymal transition, contributing to disease progression [88].

This suggests that dysregulation of this miRNA-lncRNA pair may contribute to the modulation of MC activity, potentially influencing tumor progression. These studies provide further insight into the role of miRNAs in regulating MC function and their potential involvement in the pathogenesis of MC-related diseases and tumors.

Other neoplasms

Similarly, a study by Xie et al. identified key genes and pathways associated with resting MCs in meningiomas, and constructed a prognostic model. Three key miRNAs–miR-145-5p, miR-29c-3p, and miR-335-3p are associated with the regulation of MC function in meningiomas. Dysregulation of these miRNAs may contribute to the development and progression of meningiomas and could potentially serve as prognostic markers [90]. These findings highlight the importance of investigating the role of MCs and their associated miRNAs in the pathogenesis of brain tumors.

In lung adenocarcinoma, a study focusing on the immune infiltration pattern and its relation to MCs revealed a prognostically relevant miRNA-MC network. The researchers performed extensive analyses of tumor transcriptomes and evaluated the prognostic significance of immune infiltration. The presence of resting MCs was strongly associated with improved overall and disease-free survival, whereas activated MCs were associated with poorer survival outcomes [91]. Immune infiltration-miRNA functional network analysis revealed that miRNAs associated with resting MCs were mainly involved in mRNA metabolism, bone marrow cell differentiation, and pathways such as Wnt, calcium regulation, interferon, and p53. These findings suggest that the miRNA-MC network may play a role in modulating the TME and influencing patient prognosis in lung adenocarcinoma.

In addition, in prostate cancer, tumor-infiltrating MCs regulate androgen receptor (AR)/cytokine IL-8 signaling through a positive feedback mechanism to recruit more MCs. Interestingly,,miRNA-32 inhibition can partially reverse this recruitment. This has led to the identification of the anti-androgen drug enzalutamide as being able to alter tumor-infiltrating MC/AR/miRNA-32 signaling to promote neuroendocrine differentiation in prostate cancer [83]. This study highlights the complex interactions between MCs, miRNAs, and tumor cells in the context of prostate cancer and suggests that targeting these pathways may have therapeutic potential.

Kyeonga et al. showed that miR-122 plays a critical role in counteracting the effects of tumor-derived conditioned medium on MC activation by targeting suppressor of cytokine signaling-1 (SOCS1). In addition to regulating MC activation, miR-122 inhibited the enhanced invasion and migration potential of B16F1 tumor cells induced by activated MC-conditioned medium [92]. Similarly, the transglutaminase II/miR-218/−181a and miRNA-26a/−26b-COX-2-MIP-2 negative feedback loops have been shown to regulate tumor metastasis promoted by allergic inflammation [84, 85], whereas the CAGE-miR-1405p-Wnt1 negative feedback loop regulates tumor-induced MC autophagy [86]. These studies provide insights into the complex regulatory networks involving miRNAs, MCs, and tumor cells in the context of allergic inflammation and tumor progression.

In the context of HPV-induced lesions, a study by Costa et al. in K14-HPV16 transgenic mice demonstrated an increase in MC infiltration associated with lesion progression. This process was likely supported by the regulation of chemokines in MCs by miR-223-3p and miR-125b-5p. These miRNAs may play roles in modulating the recruitment and activation of MCs in HPV-induced lesions [87]. This study suggests that targeting these miRNAs may have the potential to treat HPV-related inflammatory lesions.

Elevated levels of miRNAs such as miR-30a and miR-23a in the serum of patients with systemic mastocytosis and in mast tumor cell-derived EVs can inhibit osteogenic factors and impair osteoblast maturation and bone metabolism in the context of systemic mastocytosis [24]. miR100-5p and miR-125b in EVs released by lung cancer-activated MCs regulate p53 signaling, cancer pathways, and pathways associated with apoptosis and the cell cycle [93].

Overall, these studies highlight the complex interplay between miRNAs, MCs, and cancer cells in the context of tumor progression in various neoplasms. The authors suggest that targeting specific miRNAs or their associated pathways may have therapeutic potential to modulate the TME and influence patient outcomes.

Inflammatory diseases

In addition to their role in cancer and allergic diseases, miRNAs in MCs also regulate various disease processes, including stroke, and infection. Constitutive expression of miR-214-3p, miR-424-5p, miR-126-5p, and miR-302c-3p in tonsil-derived stem cells may be associated with significant downregulation of inflammatory cytokines, effectively alleviating TLR7-mediated skin inflammation in mice, along with an increase in the number of MCs [94]. This suggests that these miRNAs have anti-inflammatory properties and could be used to treat of inflammatory skin disorders.

In experimental mouse models of cerebral hemorrhage, ER stress is associated with MC degranulation and neuroinflammation via the IRE1α/miR-125/Lyn pathway [95]. These studies highlight the involvement of MCs and their associated miRNAs in the pathogenesis of neuroinflammatory disorders, and suggest that targeting these pathways may have therapeutic potential.

Synovial MCs in the joints of patients with rheumatoid arthritis (RA) to produce higher levels of PGD2 than those in patients with osteoarthritis. Increased PGD2 production is mediated by the miR-199a-3p/prostaglandin synthetase 2 axis. Dysregulation of this pathway may contribute to inflammation and joint damage observed in RA [96]. This study suggests that targeting the miR-199a-3p/prostaglandin synthetase 2 axis may have therapeutic potential in the treatment of inflammation and joint damage in RA.

Exosomal miR-409-3P derived from MCs can induce microglial migration by activating the NF-κB pathway targeting Nr4a2, suggesting a role for MC-associated miRNAs in neuroinflammatory disorders [97]. These studies highlight the involvement of MCs and their associated miRNAs in the pathogenesis of neuroinflammatory disorders, and suggest that targeting these pathways may have therapeutic potential.

These studies highlight the diverse roles of miRNAs in the regulation of inflammation and disease processes, including chronic inflammation, skin inflammation, cerebral hemorrhage, and neuroinflammation. These findings provide insights into the potential therapeutic applications of targeting these miRNAs for the treatment of inflammatory disorders.

Digestive tract diseases

In recent years, numerous studies have highlighted the significant impact of dysregulated miRNAs on various molecular mechanisms associated with gastrointestinal disorders [98].

For example, miR-490-5p has been implicated in the pathogenesis of irritable bowel syndrome (IBS) through its influence on MC proliferation and apoptosis. Dysregulation of miR-490-5p may potentially contribute to the altered MC activity observed in IBS, leading to gastrointestinal symptoms [99]. This suggests that miR-490-5p is a potential therapeutic target for the treatment of IBS.

MC-derived EVs have been shown to affect intestinal mucosal integrity through various miRNA-mediated pathways. For example, the NEAT1/miR-211-5p/glial cell-derived neurotrophic factor (GDNF) axis in the duodenum regulates intestinal mucosal integrity and may be dysregulated in conditions, such as functional dyspepsia [100]. In addition, miRNA-223 from MC-derived EVs can increase intestinal epithelial cell permeability and disrupt intestinal barrier function, potentially contributing to IBD pathogenesis [101]. These findings highlight the diverse roles of exosomal miRNAs released by MCs in various diseases and underscore the potential therapeutic implications of targeting miRNA-mediated pathways for the management of these diseases. Further research is essential to gain a deeper understanding of the complex interplay between MCs, exosomal miRNAs, and disease pathogenesis.

Conclusions and perspective

Recent studies on the interactions between MCs and miRNAs have provided important insights into their roles in regulating gene expression and their involvement in disease processes. Studies have revealed specific miRNA expression patterns in MCs, highlighting their importance in cellular development, activation, and function. In particular, certain miRNAs have been identified as key regulators of MC proliferation, maturation, and apoptosis as well as their participation in allergic and inflammatory responses. These findings, summarized in Fig. 2, highlight the complexity and significance of miRNAs in various diseases.

Fig. 2.

Relationship between miRNAs of MCs and diseases

miR-155 regulates MC activation and allergic diseases through cytokines and signaling pathways [67]. In CCA, miR-182/183-5p transported by EVs promotes the proliferation, invasion, and epithelial-mesenchymal transition of cancer cells [88]. miR-223-3p and miR-125b-5p play roles in modulating the recruitment and activation of MCs in HPV-induced lesions [87]. In experimental mouse models of cerebral hemorrhage, ER stress is associated with MC degranulation and neuroinflammation via the IRE1α/miR-125/Lyn pathway [95]. miR-490-5p has been implicated in the pathogenesis of irritable bowel syndrome (IBS) through its influence on MC proliferation and apoptosis. Exosomal miR-409-3P derived from MCs can induce microglial migration by activating the NF-κB pathway targeting Nr4a2, suggesting a role for MC-associated miRNAs in neuroinflammatory disorders [97]. Figure created with Figdraw.com

Despite these advances, deciphering the complex regulatory mechanisms of miRNAs in MCs remains challenging. The extensive range of miRNA functions necessitates further research to understand their impact on MC biology and associated diseases. Future studies should aim to delineate the precise molecular interactions of miRNAs in MCs, particularly their target gene interactions and their roles in disease pathogenesis. Moreover, research has predominantly relied on cell culture and murine models, with limited studies in human contexts such as asthma and rhinitis [102]. Therefore, further studies focused on human diseases, exploring miRNAs as non-invasive biomarkers for disease typing and treatment prediction and their therapeutic potential in diseases involving MCs, are required.

EVs play a role in cell-to-cell communication by transferring miRNAs and other molecules between cells. The presence of miRNA-carrying EVs in bodily fluids opens novel avenues for their use as diagnostic biomarkers for MC-associated diseases and other diseases. The study of MC-derived EVs and their miRNA content is crucial for understanding disease progression and the mechanisms underlying cell communication. In addition, the advent of exosome-based drug delivery systems has introduced a promising methodology for targeted and personalized treatment options, potentially revolutionizing therapeutic approaches for MC-related diseases.

The convergence of research on MCs, miRNAs, and EVs has led to significant advances in our understanding of disease mechanisms and the development of novel diagnostic and therapeutic methods. Ongoing research in this area is expected to yield transformative discoveries and applications in medicine and enhance diagnostics, treatments, and personalized medical strategies across a broad spectrum of diseases.

Furthermore, the metabolism and reprogramming of MCs are emerging as crucial elements in their function and response mechanisms [103–107]. The metabolic pathways in MCs extend beyond energy production and play vital roles in their activation, proliferation, and mediator secretion. miRNAs are known to play key roles in regulating gene expression, including genes involved in metabolic processes [108, 109]. Investigating the influence of miRNAs on the metabolic reprogramming of MCs is a promising research direction. Such studies can reveal novel regulatory mechanisms and therapeutic targets, shedding light on the modulation of MC function in health and disease. This focus on the interplay between miRNAs and MC metabolism holds the potential for groundbreaking insights and advancements in understanding and treating related conditions.

Author contributions

All authors contributed to the study conception and design. Material preparation, data collection and analysis were performed by Siyun Fang, Yueshan Sun, Lei Liu, Chao Li and Guangquan Li. The first draft of the manuscript was written by Qiuping Deng and Xiuju Yao. Funding acquisition, conceptualization, supervision were performed by Yuanbiao Guo and Jibo Liu. All authors commented on previous versions of the manuscript. All authors read and approved the final manuscript.

Funding

This research was supported by National Natural Science Foundation of China (81,270,465), Chengdu Medical Research Project Foundation (2,022,284).

Data Availability

No datasets were generated or analyzed during the current study.

Declarations

Conflict of Interests

The authors declare no competing interests.