Sphingosine‐1‐phosphate (S1P) induces potent anti‐inflammatory effects in vitro and in vivo by S1P receptor 4‐mediated suppression of 5‐lipoxygenase activity

ABSTRACT Sphingosine‐1‐phosphate (S1P) is involved in the regulation of important cellular processes, including immune‐cell trafficking and proliferation. Altered S1P signaling is strongly associated with inflammation, cancer progression, and atherosclerosis; however, the mechanisms underlying its pathophysiologic effects are only partially understood. This study evaluated the effects of S1P in vitro and in vivo on the biosynthesis of leukotrienes (LTs), which form a class of lipid mediators involved in the pathogenesis of inflammatory diseases. Here, we report for the first time that S1P potently suppresses LT biosynthesis in Ca 2+ ‐ionophore–stimulated intact human neutrophils. S1P treatment resulted in intracellular Ca 2+ mobilization, perinuclear translocation, and finally irreversible suicide inactivation of the LT biosynthesis key enzyme 5‐lipoxygenase (5‐LO). Agonist studies and S1P receptor mRNA expression analysis provided evidence for a S1P receptor 4–mediated effect, which was confirmed by a functional knockout of S1P4 in HL60 cells. Systemic administration of S1P in wild‐type mice decreased both macrophage and neutrophil migration in the lungs in response to LPS and significantly attenuated 5‐LO product formation, whereas these effects were abrogated in 5‐LO or S1P4 knockout mice. In summary, targeting the 5‐LO pathway is an important mechanism to explain S1P‐mediated pathophysiologic effects. Furthermore, agonism at S1P4 represents a novel effective strategy in pharmacotherapy of inflammation.—Fettel, J., Kühn, B., Guillen, N. A., Sürün, D., Peters, M., Bauer, R., Angioni, C., Geisslinger, G., Schnütgen, F., Meyer zu Heringdorf, D., Werz, O., Meybohm, P., Zacharowski, K., Steinhilber, D., Roos, J., Maier, T. J. Sphingosine‐1‐phosphate (S1P) induces potent anti‐inflammatory effects in vitro and in vivo by S1P receptor 4‐mediated suppression of 5‐lipoxygenase activity. FASEB J. 33, 1711–1726 (2019). www.fasebj.org