The Crosstalk between FcεRI and Sphingosine Signaling in Allergic Inflammation

Abstract

Sphingolipid molecules have recently attracted attention as signaling molecules in allergic inflammation diseases. Sphingosine-1-phosphate (S1P) is synthesized by two isoforms of sphingosine kinases (SPHK 1 and SPHK2) and is known to be involved in various cellular processes. S1P levels reportedly increase in allergic inflammatory diseases, such as asthma and anaphylaxis. FcεRI signaling is necessary for allergic inflammation as it can activate the SPHKs and increase the S1P level; once S1P is secreted, it can bind to the S1P receptors (S1PRs). The role of S1P signaling in various allergic diseases is discussed. Increased levels of S1P are positively associated with asthma and anaphylaxis. S1P can either induce or suppress allergic skin diseases in a context-dependent manner. The crosstalk between FcεRI and S1P/SPHK/S1PRs is discussed. The roles of the microRNAs that regulate the expression of the components of S1P signaling in allergic inflammatory diseases are also discussed. Various reports suggest the role of S1P in FcεRI-mediated mast cell (MC) activation. Thus, S1P/SPHK/S1PRs signaling can be the target for developing anti-allergy drugs.

Keywords: FcεRI signaling; allergic inflammation; micro RNAs; sphingolipids; sphingosine kinase; sphingosine signaling.

Figure 1

Metabolic pathway of sphingolipids. Sphingomyelin is present in the cell membrane and can be converted to ceramide by sphingomyelinase. Ceramidase can the convert ceramide into sphingosine, which is phosphorylated by the SPHKs and converted into S1P. Sphingosine can be converted into ceramide by ceramide synthase. S1P can be degraded into hexadecenal and ethanolamine phosphate by S1P lyase. S1P is also be subjected to extracellular transport by ABC transporters. S1P can be converted into sphingosine by sphingosine phosphate phosphatase. The arrows (black, yellow, dark yellow, and dotted) denote the direction of reactions. CS, ceramide synthase; SPP, sphingosine-1-phosphate phosphatase.

Figure 2

FcεRI signaling in allergic inflammation.

Figure 3

Crosstalk between FcεRI and S1PRs in allergic inflammation. Allergens can be bound by two molecules of IgE, resulting in dimerization of FcεRI. IgE-bound FcεRI can activate SPHKs, which in turn increase the levels of S1P. S1P undergoes extracellular transport by the ABC transporter. Extracellular S1P can bind to S1PRs, which in turn can regulate multiple signaling pathways to activate FcεRI signaling and are responsible for degranulation in MCs. The increased calcium ions by FcεRI signaling are known to induce MC granulation by increasing the secretion of histamine. Here, ↑ denotes increased level/activity, the hollow and dotted arrows denote directions of reaction, and α, β, and γ denote the subunits of FcεRI.

Figure 4

Proposed model of FcεRI-promoted allergic inflammation in relation to HDAC2/3 and S1P signaling. The hollow arrows denote the direction of reactions; the T bar arrows denote negative regulation; ↑ denotes increased level/activity; ↓ denotes decreased level/activity; Red X denotes transcription repression. Ub, ubiquitination.

Figure 5

Expression regulation of SPHK and S1PRs. (A) microRNAs that target components of S1P signaling are shown. The T bar arrows denote negative regulation. These miRNAs directly decrease the expression of SPHK1, SPHK2, S1PR1, or S1P lyases. SPHK, sphingosine kinase: S1PR1, sphingosine-1-phosphate receptor 1. (B) Potential binding sites for transcription factors in the promoter sequences of S1PRs. Here, +1 denotes the transcription start site. C/EBP, CCAAT box enhancer binding protein; ER, estrogen receptor; GATA-1, GATA binding protein 1; GR, glucocorticoid receptor; HCF, host cell factor; IFR-2, interferon regulatory factor 2; RXR, retinoid X receptor; STAT4, signal transducer and activator of transcription 4; YY1, yin yang 1. (C) TargetScan analysis reveals miRNAs that can bind to the 3′ untranslated regions (UTR) of S1PRs. Sequences in the parentheses denote sequences of miRNAs that can form base pairs with the 3′ UTRs of S1PRs. The roles of these miRNAs in allergic inflammation or the expression regulation of S1PRs have not been studied yet.