sphingosine-1-phosphate and Immune-System-Diseases

Sphingosine-1-phosphate (S1P) is a bioactive lipid metabolite that exerts its actions by engaging 5 G-protein-coupled receptors (S1PR1-S1PR5). S1P receptors are involved in several cellular and physiological events, including lymphocyte/hematopoietic cell trafficking. An S1P gradient (low in tissues, high in blood), maintained by synthetic and degradative enzymes, regulates lymphocyte trafficking. Because lymphocytes live long (which is critical for adaptive immunity) and recirculate thousands of times, the S1P-S1PR pathway is involved in the pathogenesis of immune-mediated diseases. The S1PR1 modulators lead to receptor internalization, subsequent ubiquitination, and proteasome degradation, which renders lymphocytes incapable of following the S1P gradient and prevents their access to inflammation sites. These drugs might also block lymphocyte egress from lymph nodes by inhibiting transendothelial migration. Targeting S1PRs as a therapeutic strategy was first employed for multiple sclerosis (MS), and four S1P modulators (fingolimod, siponimod, ozanimod, and ponesimod) are currently approved for its treatment. New S1PR modulators are under clinical development for MS, and their uses are being evaluated to treat other immune-mediated diseases, including inflammatory bowel disease (IBD), rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), and psoriasis. A clinical trial in patients with COVID-19 treated with ozanimod is ongoing. Ozanimod and etrasimod have shown promising results in IBD; while in phase 2 clinical trials, ponesimod has shown improvement in 77% of the patients with psoriasis. Cenerimod and amiselimod have been tested in SLE patients. Fingolimod, etrasimod, and IMMH001 have shown efficacy in RA preclinical studies. Concerns relating to S1PR modulators are leukopenia, anemia, transaminase elevation, macular edema, teratogenicity, pulmonary disorders, infections, and cardiovascular events. Furthermore, S1PR modulators exhibit different pharmacokinetics; a well-established first-dose event associated with S1PR modulators can be mitigated by gradual up-titration. In conclusion, S1P modulators represent a novel and promising therapeutic strategy for immune-mediated diseases.

Topics: Animals; Humans; Immune System Diseases; Lysophospholipids; Multiple Sclerosis; Pharmaceutical Preparations; Signal Transduction; Sphingosine

Interest in sphingosine-1-phosphate (S1P)(1) receptor agonists has increased steadily since the discovery that the mechanism of action of fingolimod (FTY-720)-induced lymphopenia is linked to the S1P GPCR family. Fingolimod is an agonist at four out of the five S1P family receptors. Adoptive cell transfer experiments and selective S1P(1) receptor agonists provided evidence that the S1P(1) receptor is the main target responsible for trapping lymphocytes in secondary lymphoid tissue. This readily accessible, translatable biomarker has been correlated with efficacy in rodent models of immune disease. Novartis AG filed for regulatory approval for fingolimod in the US and EU for the treatment of multiple sclerosis in December 2009. In addition, more selective compounds targeting S1P receptors from several companies have entered clinical trials. These compounds can be categorized into two classes of S1P(1) receptor agonists: amino alcohol prodrugs and second-generation direct agonists. This review focuses on the development of these compounds and the role of S1P receptor family selectivity.

Topics: Animals; Clinical Trials as Topic; Humans; Immune System Diseases; Lysophospholipids; Nerve Tissue Proteins; Pharmaceutical Preparations; RNA-Binding Proteins; Signal Transduction; Sphingosine

Although much is described about the molecules involved in neutrophil migration from circulation into tissues, less is known about the molecular mechanisms that regulate neutrophil entry into lymph nodes (LNs) draining a local inflammatory site. In this study, we investigated neutrophil migration toward LNs in a context of inflammation induced by immunization of BALB/c mice with OVA emulsified in CFA. We demonstrated that neutrophils can enter LNs of OVA/CFA-immunized mice not only via lymphatic vessels but also from blood, across high endothelial venules. By adoptive transfer experiments, we showed that this influx was dependent on an inflammatory-state condition and previous neutrophil stimulation with OVA/anti-OVA immune complexes. Importantly, we have demonstrated that, in the migratory pattern to LNs, neutrophils used L-selectin and P-selectin glycoprotein ligand-1, macrophage-1 Ag and LFA-1 integrins, and CXCR4 to get access across high endothelial venules, whereas macrophage-1 Ag, LFA-1, and CXCR4 were involved in their trafficking through afferent lymphatics. Strikingly, we found that stimulation with immune complexes significantly upregulated the expression of sphingosine-1-phosphate receptor 4 on neutrophils, and that treatment with the sphingosine-1-phosphate agonist FTY720 altered neutrophil LN-homing ability. These findings summarized in this article disclose the molecular pattern that controls neutrophil recruitment to LNs.

Topics: Adoptive Transfer; Animals; Antigen-Antibody Complex; Cell Movement; Female; Fingolimod Hydrochloride; Immune System Diseases; Immunosuppressive Agents; Inflammation; L-Selectin; Leukocyte Disorders; Lymph Nodes; Lymphatic Vessels; Lymphocyte Function-Associated Antigen-1; Lysophospholipids; Macrophage-1 Antigen; Mice; Mice, Inbred BALB C; Neutrophils; P-Selectin; Propylene Glycols; Receptors, CXCR4; Receptors, Lysosphingolipid; Sphingosine