S1P signaling is pivotal to pathological processes associated with autoimmune diseases, cancer and cardiovascular conditions, which has significant implications for the treatment of these diseases.
In treatments for autoimmune diseases such as multiple sclerosis, S1P signaling is targeted to prevent lymphocytes from migrating from the lymph nodes into inflammation sites, thereby reducing inflammation and autoimmunity. S1P receptor modulators, like fingolimod, siponimod, ozanimod and ponesimod, are currently approved for treating multiple sclerosis and more are being studied for treating other immune-mediated diseases, including inflammatory bowel disease (IBD), rheumatoid arthritis (RA), systemic lupus erythematosus (SLE) and psoriasis (17).
In cancer, S1P signaling promotes cancer cell growth, metastasis, survival and immune tolerance to the tumor microenvironment. S1PR1 signaling can also trigger the activation of other signaling pathways involved in carcinogenesis, including PI3K/AKT, MAPK/ERK1/2, Rac and PKC/Ca. Modulating S1P signaling can disrupt processes involved in cancer progression, making S1PR signaling a potential anti-tumor therapeutic target (18).
SIP signaling regulates cardiovascular-related functions, including endothelial function, cardiac contractility, cardiac homeostasis and vascular tone, by binding and activating S1PR1, S1PR2 and S1PR3 expressed in endothelial and smooth muscle cells, cardiomyocytes and fibroblasts. Dysregulated S1P signaling is implicated in cardiovascular diseases, including arterial hypertension and atherosclerosis. Selective S1P receptor modulators are being investigated to promote protective cardiovascular effects while minimizing adverse outcomes (19).