sphingosine-1-phosphate and Anaphylaxis

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.

Topics: Anaphylaxis; Asthma; Humans; Inflammation; Receptors, IgE; Sphingosine

Anaphylaxis is the most concerning manifestation of hypersensitivity. Recent thorough investigations on the pathophysiology of anaphylaxis achieved important advances in its understanding, regarding in particular the emerging role of mediators such as platelet activating factor (PAF) and sphyngosine 1 phosphate (S1P) and the improved knowledge on the actors of the signaling cascade, from the contact between the specific allergen and the IgE fixed on the Fc-epsilon-RI receptor to the opening of calcium channels. These advances may provide new diagnostic and therapeutical tools. In particular, a role for PAF and S1P as laboratory markers of anaphylaxis is likely to be developed, and innovative preventive strategies able to induce a negative signaling are currently under evaluation. Also, using well known preventive treatments, such as allergen specific immunotherapy may offer new perspectives for the management of patients at risk of potentially fatal reaction to foods. In fact, controlled studies demonstrated that sublingual immunotherapy is able to significantly increase the tolerance to the causative foods, fulfilling the need and protecting the allergic subject from anaphylaxis caused by accidental ingestion of small food amounts. The article also presented some promising patents on anaphylaxis.

Topics: Anaphylaxis; Animals; Food Hypersensitivity; Humans; Immunotherapy; Lysophospholipids; Patents as Topic; Platelet Activating Factor; Signal Transduction; Sphingosine

The present review considers recent reports that identify the roles of key intermediate signaling components and mediators during and after mast cell activation and degranulation leading to anaphylaxis.. Mechanisms of anaphylaxis are becoming better understood as the interaction of several regulatory systems in the mast cell activation and degranulation signaling cascade. Multiple tyrosine kinases, activated after immunoglobulin E binding to the high-affinity receptors for immunoglobulin E (FcepsilonRI), exert both positive and negative regulation on the signaling cascade, which may vary with genetic background or mutations in signaling proteins. Calcium influx, the essential, proximal intracellular event leading to mast cell degranulation, is controlled also by both negative and positive regulation through calcium channels. Sphingosine-1-phosphate is emerging as a newly realized mediator of anaphylaxis, acting as a signaling component within the mast cell and as a circulating mediator.. Anaphylaxis is a systemic reaction involving multiple organ systems, but it is believed that it may be influenced by cellular events in mast cells and basophils resulting in the release of mediators. Therefore, understanding the mechanisms of mast cell activation and degranulation is critical to understanding the mechanisms of anaphylaxis. Recent reports have identified important regulatory components of the signaling cascade and, consequently, potential targets for therapeutic intervention.

Topics: Anaphylaxis; Animals; Calcium Channels; Cell Degranulation; Humans; Immunoglobulin E; Inflammation Mediators; Lysophospholipids; Mast Cells; Mastocytosis, Systemic; Mice; Proto-Oncogene Proteins c-fyn; Signal Transduction; Sphingosine; src-Family Kinases

Pharmacological interference with sphingolipid metabolizing enzymes promises to provide novel ways to modulate cellular pathways relevant in multiple diseases. In this review, we focus on two sphingolipid signaling molecules, sphingosine-1-phosphate (S1P) and ceramide, as they are involved in cell fate decisions (survival vs. apoptosis) and in a wide range of pathophysiological processes. For S1P, we will discuss sphingosine kinases and S1P lyase as the enzymes which are crucial for its production and degradation, respectively, emphasizing the potential therapeutic usefulness of inhibitors of these enzymes. For ceramide, we will concentrate on acid sphingomyelinase, and critically review the substantial literature which implicates this enzyme as a worthwhile target for pharmacological inhibitors. It will become clear that the task to validate these enzymes as drug targets is not finished and many questions regarding the therapeutic usefulness of their inhibitors remain unanswered. Still this approach holds promise for a number of totally new therapies, and, on the way, detailed insight into sphingolipid signaling pathways can be gained.

Topics: Aldehyde-Lyases; Anaphylaxis; Animals; Apoptosis; Atherosclerosis; Bacterial Infections; Ceramides; Cyclooxygenase 2; Dendritic Cells; Drug Design; Enzyme Inhibitors; Humans; Immunologic Factors; Leukocytes; Lysophospholipids; Macrophages; Mast Cells; Neoplasms; Neovascularization, Pathologic; Phosphotransferases (Alcohol Group Acceptor); RNA, Small Interfering; Sphingolipids; Sphingomyelin Phosphodiesterase; Sphingosine

Sphingosine-1-phosphate (S1P) is a bioactive sphingolipid metabolite that plays important roles in allergic responses, including asthma and anaphylaxis, the incidence of which is rising worldwide especially in industrialized urban populations. In this review, we will discuss how S1P is formed and released, and how it acts at many cellular levels, including mast cells, the airway epithelium, airway smooth muscle and many immune cells. Since the actions of S1P on all of these cells could exacerbate allergic responses, the proteins that synthesize, release and respond to S1P offer plausible targets for a new generation of antiinflammatory therapeutics.

Topics: Anaphylaxis; Animals; Asthma; Drug Delivery Systems; Humans; Lysophospholipids; Mast Cells; Receptors, Lysosphingolipid; Respiratory Mucosa; Sphingosine

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.

Topics: Anaphylaxis; Animals; Humans; Lysophospholipids; Mast Cells; Models, Biological; Phosphotransferases (Alcohol Group Acceptor); Receptors, Lysosphingolipid; Sphingosine

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.

Topics: Anaphylaxis; Animals; Antibodies, Monoclonal; Asthma; Drug Delivery Systems; Humans; Hypersensitivity; Lysophospholipids; Mast Cells; Receptors, Lysosphingolipid; Sphingosine

Sphingosine-1-phosphate (S1P) signaling is essential for vascular development and postnatal vascular homeostasis. The relative importance of S1P sources sustaining these processes remains unclear.. To address the level of redundancy in bioactive S1P provision to the developing and mature vasculature.. S1P production was selectively impaired in mouse platelets, erythrocytes, endothelium, or smooth muscle cells by targeted deletion of genes encoding sphingosine kinases -1 and -2. S1P deficiency impaired aggregation and spreading of washed platelets and profoundly reduced their capacity to promote endothelial barrier function ex vivo. However, and in contrast to recent reports, neither platelets nor any other source of S1P was essential for vascular development, vascular integrity, or hemostasis/thrombosis. Yet rapid and profound depletion of plasma S1P during systemic anaphylaxis rendered both platelet- and erythrocyte-derived S1P essential for survival, with a contribution from blood endothelium observed only in the absence of circulating sources. Recovery was sensitive to aspirin in mice with but not without platelet S1P, suggesting that platelet activation and stimulus-response coupling is needed. S1P deficiency aggravated vasoplegia in this model, arguing a vital role for S1P in maintaining vascular resistance during recovery from circulatory shock. Accordingly, the S1P2 receptor mediated most of the survival benefit of S1P, whereas the endothelial S1P1 receptor was dispensable for survival despite its importance for maintaining vascular integrity.. Although source redundancy normally secures essential S1P signaling in developing and mature blood vessels, profound depletion of plasma S1P renders both erythrocyte and platelet S1P pools necessary for recovery and high basal plasma S1P levels protective during anaphylactic shock.

Topics: Anaphylaxis; Animals; Blood Platelets; Blood Vessels; Endothelium, Vascular; Erythrocytes; Homeostasis; Human Umbilical Vein Endothelial Cells; Humans; Lysophospholipids; Mice; Mice, 129 Strain; Mice, Inbred C57BL; Mice, Transgenic; Sphingosine

IgE-mediated mast cell degranulation and release of vasoactive mediators induced by allergens elicits allergic responses. Although G protein-coupled receptor (GPCR)-induced signals may amplify IgE-dependent degranulation, how GPCR signaling in mast cells is regulated remains incompletely defined. We investigated the role of regulator of G protein signaling (RGS) proteins in the modulation of these pathways in human mast cells. Several RGS proteins were expressed in mast cells including RGS13, which we previously showed inhibited IgE-mediated mast cell degranulation and anaphylaxis in mice. To characterize how RGS13 affects GPCR-mediated functions of human mast cells, we analyzed human mast cell lines (HMC-1 and LAD2) depleted of RGS13 by specific small interfering RNA or short hairpin RNA and HMC-1 cells overexpressing RGS13. Transient RGS13 knockdown in LAD2 cells lead to increased degranulation to sphingosine-1-phosphate but not to IgE-Ag or C3a. Relative to control cells, HMC-1 cells stably expressing RGS13-targeted short hairpin RNA had greater Ca(2+) mobilization in response to several natural GPCR ligands such as adenosine, C5a, sphingosine-1-phosphate, and CXCL12 than wild-type cells. Akt phosphorylation, chemotaxis, and cytokine (IL-8) secretion induced by CXCL12 were also greater in short hairpin RGS13-HMC-1 cells compared with control. RGS13 overexpression inhibited CXCL12-evoked Ca(2+) mobilization, Akt phosphorylation and chemotaxis. These results suggest that RGS13 restricts certain GPCR-mediated biological responses of human mast cells.

Topics: Adenosine; Allergens; Anaphylaxis; Animals; Antigens; Calcium; Cell Degranulation; Cell Line; Chemokine CXCL12; Chemotaxis; Complement C5a; Humans; Immunoglobulin E; Interleukin-8; Ligands; Lysophospholipids; Mast Cells; Mice; Phosphorylation; Proto-Oncogene Proteins c-akt; Receptors, G-Protein-Coupled; RGS Proteins; RNA, Small Interfering; Sphingosine

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.

Topics: Anaphylaxis; Animals; Biomarkers; Lysophospholipids; Mast Cells; Mice; Mice, Mutant Strains; Phosphotransferases (Alcohol Group Acceptor); Sphingosine