Sphingosine 1‐phosphate induces anti‐inflammatory M2 polarization through IL‐4 signaling in macrophages (662.14)

Abstract

Phenotypes of macrophages, classic pro‐inflammatory M1 and alternative anti‐inflammatory M2, could influence many disease states like atherosclerosis. Lipopolysaccharide (LPS)‐activated macrophages increase pro‐inflammatory cytokine secretion. Such LPS‐induced‐M1 phenotype expression was suppressed by sphingosine 1‐phosphate (S1P), an anti‐atherogenic lipid mediator in HDL. Previously, suppression of NF‐κB activity through S1P1 was suggested as a key mechanism for the suppression of M1 phenotype (Hughes et al. Circ Res. 2008; 102: 950‐958). In the present study, we addressed how S1P induces M2 macrophage polarization in mouse macrophages and found that S1P induced anti‐inflammatory M2 polarization through IL‐4 secretion and its signaling. S1P induced not only induction and secretion of IL‐4 but also induction of their receptors, IL‐4Rα and IL‐2Rγ. In addition, down‐stream signaling such as phosphorylation of stat‐6, induction of SOCS1, and suppression of SOCS3 expression was also observed in response to S1P. Furthermore, S1P‐induced activation of ERK and inhibition of p38 MAPK and JNK were found to be key signaling for IL‐4 induction. Present data suggest that anti‐atherogenic effect of S1P in HDL may be mediated through IL‐4 secretion and its phenotype switching from M1 to M2 anti‐inflammatory macrophages.Grant Funding Source: This research was supported by Basic Science Research Program through the NRF (2011‐0021158)