Mast cells (MCs) are best known to trigger IgE-dependent/independent allergic diseases. They also play a significant role in providing immunity to host in response to various infections (1). MCs have enough storage of bioactive molecules and mediators to perform innate and adaptive immune responses. However, the same bioactive molecules may damage the surrounding tissues and cause inflammation. MCs can be activated by diverse stimuli including allergens, pollens, and toxins and may release a spectrum of molecules, including preformed mediators (such as histamine, proteases, and other enzymes). They are accountable for numerous symptoms of allergic reactions including edema and enhanced vascular permeability (2). MCs release variety of cytokines (e.g., IL-4, IL-5, and IL-13) and chemokines that are responsible for recruitment and maturation of different immune cells. In addition, MCs synthesize and release variety of lipid mediators such as prostaglandins, leukotrienes, platelet-activating factor, and sphingosine-1-phosphate (S1P) (3). S1P mediates its actions both by acting as a ligand for five S1P receptors and also an intracellular second messenger (4). It is also known to play an important role in numerous pathophysiological responses including allergic reactions such as asthma and chronic obstructive pulmonary disease (COPD).

Two highly homologous sphingosine kinases (SphKs), known as sphingosine kinase 1 (SphK1) and sphingosine kinase 2 (SphK2) catalyze the synthesis of S1P from its precursor sphingosine (Figure 1) (4). SphK1 is mainly localized in the cytosol. Activation of SphK1 is regulated by many factors such as its intracellular localization, epigenetic, or posttranslational modification. SphK1 can be activated by a wide variety of growth factors, including epidermal growth factor, platelet-derived growth factor (PDGF), vascular endothelial growth factor, hepatocyte growth factor, and TNF-α (5). Unlike SphK1, SphK2 is localized in the nucleus and mitochondria-associated outer membrane (6, 7).

Circulating and tissue S1P levels are also regulated by its catabolism. There are six enzymes known to catabolize S1P. Two endoplasmic reticulum-bound, S1P-specific phosphatases, namely, S1P phosphatase-1 and -2 dephosphorylate S1P back to sphingosine. Three lipid phosphate phosphatases-1, -2 and -3 (LPP1–3) dephosphorylate a broad range of lipid phosphate substrates including S1P (8, 9). LPPs are located on the plasma membrane. Additionally, S1P lyase irreversibly degrades S1P to ethanolamine phosphate and trans-2-hexadecenal (10).

Till date, five S1P receptors (S1PR1–5) that bind to S1P have been identified in vertebrates (11). In mammalian cells, S1P receptors are ubiquitous, but their expression patterns vary among the different tissues. After coupling to G-proteins, these receptors either activate or inhibit downstream signaling pathways, including c-Jun N-terminal kinase, extracellular signal-regulated kinase, phosphatidylinositol 3-kinase, phospholipase C, phospholipase D, STAT3, Rho, Rac, and cyclic AMP (4). By activating these receptors, S1P regulates diverse biological processes including vascular development, angiogenesis, and immunity.

Asthma may occur due to allergic/non-allergic reactions based on production of IgE antibodies to common environmental allergens (34). MCs, T lymphocytes, and eosinophils together with the resident airway cells interact with one another to perpetuate airway inflammation, leading to AHR and remodeling (35). A subset of human lung MCs, expressing CD88 receptor get activated by C5a ligand (36). Various autocoid mediators are released from activated MCs that may induce bronchoconstriction, vascular permeability, recruitment of inflammatory cells, mucous secretion, and tissue edema (35). The correlation between inflammatory cells and airway smooth muscle (ASM) cells plays a fundamental role in the pathophysiology of asthma. MCs from asthmatic patients have been shown to localize in the intercellular spaces of bronchial epithelium, ASM cells, and airway mucous glands. Thus, the disordered airway physiology and wall remodeling features of asthma are consequences of inflammation and bronchial hyperresponsiveness. In response to allergen challenge, activated MCs release inflammatory cytokines and other mediators that affect bronchial epithelial functions. Furthermore, it has been suggested that the density of MCs within the mucous gland influences the degree of mucus obstruction in the airway. MC-derived inflammatory cytokines also contribute to several features of asthma (35).

Extracellular S1P not only affects eosinophil infiltration of the airway wall but also stimulate the contractions of ASM by inducing calcium mobilization and augmenting the production of inflammatory cytokines. Moreover, S1P disrupts the epithelial cell barrier integrity (tight junctions) in the respiratory system (37–39). In peripheral airways, activation of cholinergic receptors, particularly muscarinic receptor, is associated with asthma and COPD. In mice, SphK1 has been shown to localize in the ASM of the peripheral airways. Furthermore, inhibition of SphK enzyme activity reduces muscarine-induced peripheral airway constriction, implying that the S1P signaling pathway contributes to cholinergic constriction of peripheral airways (40). Elevated levels of S1P have been observed in bronchoalveolar lavage (BAL) fluid of asthmatic patients, suggesting an important role of S1P in MC-dependent inflammatory responses in allergic reactions (38). S1P also acts as a chemotactic agent for eosinophils through RANTES and CCR3, further implying an involvement of S1P in the pathophysiology of asthma (41). Moreover, eosinophil numbers correlate with S1P levels in BAL of asthmatic patients (38). Antigen-stimulated MCs release S1P into interstitium, which may significantly modulate inflammatory processes. Interestingly, treatment with SphK inhibitor improves immune responses in mouse model of asthma (42).

In ovalbumin (OVA)-sensitized mice, S1P/SphK pathway triggers airway hyperresponsiveness (43). Furthermore, intratracheal instillation of FTY720 into mice reduces antigen-induced airway inflammation and hyperresponsiveness (44). On contrary, in asthmatic mouse model, intranasal S1P treatment results in exacerbation of antigen-induced airway inflammation and increased sensitivity to methacholine (45). Disodium cromoglycate (DSCG) treatment inhibits S1P-induced asthma-like features in mice. DSCG decreases the recruitment of MCs and B cells in the lung and reduces the levels of serum IgE, prostaglandin D₂, mucus production, and IL-13 (46). S1P-stimulated ASM cells release elevated levels of IL-6 and RANTES (47). Furthermore, S1P administration to BALB/c mice increases ASM sensitivity, mucus production, and release of IgE, PGD₂, IL-13 and IL-4, and increased recruitment of MCs to the lung (41). In MC-deficient mice, S1P does not induce bronchial hyperresponsiveness, suggesting that MCs are essential for S1P-induced bronchial hyperreactivity. Furthermore, S1P induces lung inflammation and ASM hyperreactivity in an IgE-dependent manner (41). Interestingly, in nude mice, S1P does not induce bronchial AHR, IgE release, and pulmonary infiltration of MCs. These data suggest that S1P-induced ASM hyperreactivity is T-cell dependent. Reconstitution of CD4⁺ T cells, isolated from S1P-treated mice to naïve (untreated) mice, recapitulated the ASM reactivity (41). Pre-exposure of S1P enhances methacholine-induced contraction of isolated ASM by Ca²⁺ sensitization via inactivation of RhoA-mediated myosin phosphatase (39). In a murine model of chronic asthma, SK1-I, a specific inhibitor of SphK1, significantly reduces OVA-induced AHR to methacholine. SK1-I also decreases eosinophil numbers and levels of different cytokines such as IL-4, IL-5, IL-6, IL-13, IFN-γ, and TNF-α and the chemokines, such as eotaxin, and CCL2 in BAL fluid (48).

Recently, non-coding RNAs (miRNAs and long non-coding RNAs) emerge as a crucial regulator of MCs development and play an important role in allergic diseases and bronchial asthma. Loss of dicer function in mouse MC progenitor cells results in profound disruption of tissue MC compartments, suggesting a critical role for miRNAs in MC differentiation, growth, and migration (49). miR-221 has been shown to regulate the cell cycle and cytoskeleton development process in MCs, while in response to stimulation through IgE-antigen complexes, miR-221 shows MCs’ specific effect and leads to degranulation and cytokine release (50). Higher expression (~3-fold) of miR-221 has also been reported in a murine lung asthma model compared to control mice (51). A potential increase in expression of miR-221 was also noted in P815 mouse MCs after lipopolysaccharide stimulation (51). In addition, the authors further demonstrated that miR-221 overexpression increases total cells and eosinophil numbers in the murine asthma model and stimulates IL-4 secretion in MCs through PTEN, p38, and NF-κB pathways. Upregulation of miR-221 and miR-485-3p has been reported in the peripheral blood mononuclear cells of pediatric asthmatic patients (n = 6), compared to control-group children. Similarly, upregulation (~3-fold) of miR-221 and miR-485-3p has been noted in the lungs of OVA-induced asthmatic mouse model and resulting into decreased levels of their target gene, Spred-2 (52). In a separate study, it was shown that inhibition of miRNA-221 suppresses the airway inflammation in asthmatic mouse model (53). These findings suggest that miR-221 might play an important role in the onset and development of asthma. Similarly, miR-21 also been shown to be upregulated in the multiple asthmatic mouse models induced by house dust mite, OVA, or Aspergillus fumigatus (54). miR-21 also suppresses TLR2 signaling pathways in inflammatory lung mouse model (55). In addition, miR-21 is also upregulated in IL-13-treated primary normal human airway epithelial cells. There are only few dedicated studies investigating the role of long non-coding RNA (lncRNA) in asthma. In this context, Zhang et al. have detected around 3.5-fold higher expression of BCYRN1 lncRNA in the ASM cells of the asthmatic rat model, compared to control group. In addition, BCYRN1 level increases in ASM cells in the presence of PDGF. Furthermore, BCYRN1 promotes the proliferation and migration of ASM cells via upregulating the expression of transient receptor potential 1 (TRPC1) protein through increasing the stability of TRPC1 (56). The overexpression of TRPC1 reversed the function of si-BCYRN1 in decreasing viability/proliferation and migration of ASM cells. Recently, plasmacytoma variant translocation (PVT1), another lncRNA, has been shown to decrease in ASM of patients with corticosteroid-sensitive non-severe asthma. However, its levels are increased in the patients with corticosteroid-insensitive severe asthmatic patients (57). Furthermore, the authors have shown that PVT1 regulates both IL-6 release and TGF-β-induced proliferative response in ASM cell in severe asthmatic patients. Similarly, growth arrest specific 5 lncRNA has been demonstrated to correlate with the corticosteroid response in severe asthmatic patients (58).

Several miRNAs have been demonstrated to target the components of the S1P signaling pathway (Table 1). For example, miR-124 and miR-506 target SphK1 (55, 59, 60), miR-130a-3p and miR-613 target SphK2 (61, 62), and miR-125b-1-3p, miR-133b, and miR-363 target S1PR1 (63–65), whereas miR-125b (66) binds to the S1P lyase mRNA transcript. However, the role of above miRNAs has not been elucidated in MC functions and need to be further investigated to explore the interaction between miRNA and S1P signaling pathway.

Sphingosine-1-phosphate is a dual regulator of the systemic allergic responses. It is an essential signaling molecule generated upon IgE-FcεRI crosslinking and enhances the activation of MCs in allergic diseases such as asthma. On the other hand, S1P signaling through its receptors is required for recovery from anaphylactic shock. The role of non-coding RNAs is well explored in cancer; however, their role in allergy and inflammation is still in infancy, and their role needs to be explored as a potential therapeutic target and biomarker for asthma.

RS, AK, MJ, SG, and AJ designed the manuscript; were involved in drafting/revising the manuscript; and read and approved the final manuscript. RS, AK, and AJ wrote the first draft.

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.