Sphingosine-1-phosphate modulators in inflammatory skin diseases – lining up for clinical translation

The bioactive lysophospholipid sphingosine-1-phosphate (S1P) is best known for its activity as T-cell-active chemoattractant regulating the egress of T cells from the lymph node and, consequently, the availability of T cells for migration into peripheral tissues. This physiological role of S1P is exploited by the drug fingolimod, a first-line therapy for multiple sclerosis, which "detains" T cells in the lymph nodes. In recent year, it has been elucidated that S1P exerts regulatory functions far beyond T-cell egress from the lymph node. Thus, it additionally regulates, among others, homing of several immune cell populations into peripheral tissues under inflammatory conditions. In addition, evidence, mostly derived from mouse models, has accumulated that S1P may be involved in the pathogenesis of several inflammatory skin disorder and that S1P receptor modulators applied topically are effective in treating skin diseases. These recent developments highlight the pharmacological modulation of the S1P/S1P receptor system as a potential new therapeutic strategy for a plethora of inflammatory skin diseases. The impact of S1P receptor modulation on inflammatory skin diseases next requires testing in human patients.