The Sphingosine Kinase-Sphingosine-1-Phosphate Axis Is a Determinant of Mast Cell Function and Anaphylaxis

Abstract

Sphingosine-1-phosphate, a key mediator in immune cell trafficking, is elevated in the lungs of asthmatic patients and regulates pulmonary epithelium permeability. Stimulation of mast cells by allergens induces two mammalian sphingosine kinases (Sphk1 and Sphk2) to produce sphingosine-1-phosphate (S1P). Little is known about the individual role of these kinases in regulating immune cell function. Here we show that in mast cells, Sphk2 is required for production of S1P, for calcium influx, for activation of protein kinase C, and for cytokine production and degranulation. However, susceptibility to in vivo anaphylaxis is determined both by S1P within the mast cell compartment and by circulating S1P generated by Sphk1 predominantly from a non-mast cell source(s). Thus, sphingosine kinases are determinants of mast cell responsiveness, demonstrating a previously unrecognized relationship with anaphylaxis.

Distinct roles of sphingosine kinases 1 and 2 in human mast-cell functions

“…This observation is reminiscent of the dependency on SphK2 expression for TNF-␣ secretion by fetal mouse liver-derived mast cells. 10 These results indicate that SphK2 might play an important role in regulation of release of this cytokine that is important for exacerbation of allergic responses and is overproduced in asthmatic subjects. 30 Altogether, our study reinforces the notion that SphK1 and S1P are critical for hMC activation and functions that have been implicated in allergic responses, such as asthma and anaphylaxis.…”

“…9 Based on results with fetal liver-derived MCs from SphK1 Ϫ/Ϫ , SphK2 Ϫ/Ϫ , and SphK1 Ϫ/Ϫ SphK2 Ϫ/Ϫ mice, it was suggested that SphK2, but not SphK1, may modulate calcium influx and downstream signaling, particularly PKC␣ and ␤, leading to degranulation and the production of eicosanoids and cytokines. 10 By contrast, passive systemic anaphylaxis was impaired in SphK1 Ϫ/Ϫ mice, but not in SphK2 Ϫ/Ϫ mice, and plasma histamine levels were correlated with SphK1 expression and circulating levels of S1P. Hence, it was suggested that SphK2 is a determinant of intrinsic MC function, whereas SphK1 plays an extrinsic role.…”

“…Hence, it was suggested that SphK2 is a determinant of intrinsic MC function, whereas SphK1 plays an extrinsic role. 10,11 Nonetheless, given the differences in the gene expression profiles and functional differences between human and mouse MCs (reviewed in Bischoff 12 ), SphK1 and SphK2 may play different roles in human MCs. 6 Not much is known of the functions of SphK1 and SphK2 in human MCs, and only few studies have been focused on the potential roles of S1P in human MCs.…”

“…Moreover, although circulating S1P levels were primarily determined by SphK1 expression outside of the mast-cell compartment, they correlated with histamine release and anaphylaxis. 10 The exquisite sensitivity of human mast cells to extracellular S1P suggests that even small increases in circulating S1P could enhance and amplify their degranulation and as a consequence, allergic responses. Interestingly, S1P administration via the airways but not via the vasculature induces lung leakage and it has been suggested that spatially and mechanistically distinct S1P receptor subtypes have opposing effects on pulmonary epithelial and endothelial barrier functions.…”

Sphingolipids and membrane biology as determined from genetic models

“…In addition, circulating S1P (generated mostly by SphK1) and intrinsic mast cell SPHK2 together determine the anaphylactic response, a phenomenon that involves degranulation, which is a specialized form of exocytosis. SphK2-null mice show defective PKC translocation, NF-κB activation, and calcium influx, which are all part of the regular anaphylactic response [190]. SphK1 -/-SphK2 -/-double mutants die as embryos, although the embryos appear normal until E9.5.…”