Unraveling the complexities of sphingosine-1-phosphate function: The mast cell model

Abstract

Sphingosine-1-phosphate (S1P) is a lipid mediator involved in diverse biological processes, from vascular and neural development to the regulation of lymphocyte trafficking. Many of its functions are regulated by five widely expressed S1P G-protein-coupled receptors (S1P(1-5)). S1P is produced mostly intracellularly, thus, much of its potential as an autocrine and paracrine mediator depends on how, when, and where it is generated or secreted out of the cells. However, S1P can also have intracellular activity independent of its receptors, adding to the complexity of S1P function. The mast cell, a major effector cell during an allergic response, has proven instrumental towards understanding the complex regulation and function of S1P. Antigen (Ag) engagement of the IgE receptor in mast cells stimulates sphingosine kinases, which generate S1P and are involved in the activation of calcium fluxes critical for mast cell responses. In addition, mast cells secrete considerable amounts of S1P upon activation, thus affecting the surrounding tissues and recruiting inflammatory cells. Export of S1P is also involved in the autocrine transactivation of S1P receptors present in mast cells. The in vivo response of mast cells, however, is not strictly dependent on their ability to generate S1P, but they are also affected by changes in S1P in the environment previous to Ag challenge. This review will discuss the recent advances towards understanding the intricacies of S1P generation, secretion and regulation in mast cells. In addition, how S1P receptors are activated and their involvement in mast cell functions will also be covered, including new insights on the role of S1P in the mast cell-mediated allergic response of systemic anaphylaxis.

A Novel Function of Sphingosine Kinase 1 Suppression of JNK Activity in Preventing Inflammation and Injury

“…The two forms of sphingosine kinases (SphKs), SphK1 and SphK2, have received considerable attention because of their poorly understood functions that are distinct from their catalytic function needed for the production of S1P (43)(44)(45)(46). Although SphKs may play a role in mediating inflammation seen in asthma (43)(44)(45)(46)(47), SphK1 also has a protective function in LPS-and platelet-activating factor-induced lung inflammation (35,48,49). This function may be independent of the S1P production.…”

Shaping the landscape: Metabolic regulation of S1P gradients

“…Similarly, as explained above, stromal or cancer cells can respond to these environmental cues to turn on the production of S1P while attenuating its degradation. Furthermore, the mast cell, an innate-immune, tissue-resident cell that provides host defense against pathogens and is also found in association with tumors [132], constitutes another likely candidate for altering S1P homeostasis in the interstitial tissue, particularly in allergic inflammation [133, 134]. Mast cells are considered effector cells, particularly in IgE-associated immune responses, by releasing a plethora of modulators of the immune response [132, 135].…”

“…Mast cells are considered effector cells, particularly in IgE-associated immune responses, by releasing a plethora of modulators of the immune response [132, 135]. S1P can attract mast cells to the site [136], which in turn can release large amounts of S1P when activated by antigen via Fc epsilon RI, the high affinity receptor for IgE, and possibly other signals [133]. Unlike blood cells such as red blood cells and platelets, mast cells do not store S1P, and the levels of S1P in these cells are low.…”

Recruitment of sphingosine kinase to presynaptic terminals by a conserved muscarinic signaling pathway promotes neurotransmitter release

“…Gene knockout of the SphK1 isoform impairs hippocampal long-term potentiation, spatial learning, and memory, and nociceptive processing (Mizugishi et al 2005;Kanno et al 2010), and selective inhibition of SphKs reduces glutamate secretion in cultured neurons (Kajimoto et al 2007). The generation of S1P by SphKs elicits the secretion of neurotransmitters from a variety of neurons and neurosecretory cells (Alemany et al 2001;Brailoiu et al 2002;Pan et al 2006;Kajimoto et al 2007;Olivera 2008) and modulates sensory neuron excitability (Nicol 2008). In addition, SPH has been shown to have functions in synaptic vesicle (SV) exocytosis and SV cycling (Rohrbough et al 2004;Nicol 2008;Camoletto et al 2009;Darios et al 2009).…”