Sphingosine-1-phosphate in allergic responses, asthma and anaphylaxis

Abstract

Sphingosine-1-phosphate (S1P) is a bioactive sphingolipid metabolite involved in many cellular processes, acting not only as an extracellular ligand to its specific G protein-coupled receptors, but also as a putative intracellular messenger with yet unidentified targets. Mast cells are tissue-dwelling pivotal early effectors of allergic responses, which produce and secrete S1P that can bind to its receptors present on mast cells to influence their activation and functions. In this review, we will first discuss the current knowledge of S1P production by two isozymes of sphingosine kinase (SphK). Mechanisms of SphK activation will be discussed, with an emphasis on experimental approaches developed to study their differential activation and biological roles in the context of mast cells. The relevance of mast cells in the etiology of allergic disorders, asthma and anaphylaxis is well established. In this review, this concept will be revisited, focusing on the contribution of S1P production and secretion to the symptoms associated with dysregulated inflammatory responses. To conclude, counteracting the proinflammatory effects of S1P could be envisioned as a therapeutic strategy to treat allergic disorders, exacerbated airway inflammation, and anaphylactic reactions, and various options will be discussed, such as the development of pharmacological tools to inhibit SphKs, S1P neutralizing monoclonal antibody, and S1P receptor antagonists.

Figure 1. Sphingolipid metabolites and their effects on mast cell functions

The scheme shows the structures of the bioactive sphingolipid metabolites, sphingosine, sphingosine-1-phosphate, ceramide, and ceramide-1-phosphate and indicates the enzymes responsible for their interconversion. Some important actions regulated by these metabolites in mast cells are indicated.

Figure 2. Actions of S1P in Mast Cell Functions

Crosslinking of FcεRI by antigen causes activation of the tyrosine kinases Lyn and Fyn that in turn stimulate SphK1 and SphK2 leading to formation of S1P. S1P formed by activation of SphK1 can then be exported by ABCC1 transporter to activate S1P receptors on the mast cell surface. S1P₁ is important for mast cell migration toward Ag while S1P₂ is involved in their degranulation. SphK2 acts internally to regulate calcium homeostasis and PKC, and thus regulates degranulation and release of other lipid mediators and cytokines, probably by regulating the balance between the counteracting sphingolipids, sphingosine and S1P.

Figure 3. Multiple Functions of Mast Cell-Derived S1P in Allergic Inflammation

Secretion of S1P by activated mast cells can promote allergic reactions on a broad scale by activating and recruiting many types of immune cells involved in allergic and inflammatory responses, including eosinophils (Roviezzo et al., 2004), Th2 lymphocytes (Sawicka et al., 2003) and neutrophils. S1P also profoundly affects endothelial cell function and promotes adhesion molecule expression in endothelial cells (Garcia et al., 2001; Lee et al., 1999; Wang et al., 1999; Xia et al., 1998), induces contraction and proliferation of airway smooth muscle cells (Ammit et al., 2001), fibroblast proliferation, and shifts maturing dendritic cell-induced polarization of T cells into a Th2 phenotype (Idzko et al., 2002).