Sphingosine 1-phosphate induced anti-atherogenic and atheroprotective M2 macrophage polarization through IL-4

Sphingosine 1-phosphate (SIP) has been implicated in anti-atherogenic properties of high-density lipoproteins. However, the roles and signaling of SIP in macrophages, the main contributor to atherosclerosis, have not been well studied. Furthermore, pro-inflammatory M1 and anti-inflammatory M2 macrophage phenotypes may influence the development of atherosclerosis. Therefore, we investigated the effects of SW on macrophage phenotypes, especially on M2 polarization and its signaling in relation to the anti-atherogenic properties of SIP. It was found that SW induced anti-inflammatory M2 polarization via IL-4 secretion and its signaling, and induced IL-4R alpha and IL-2R gamma. In addition, down-stream signalings, such as, stat-6 phosphorylation, SOCS1 induction, and SOCS3 suppression were also observed in macrophages in response to SIP. Furthermore, SIP-induced ERK activation, and the inhibitions of p38 MAPK and JNK were found to be key signals for IL-4 induction. Moreover, the anti-atherogenic effect of SIP in HDL was confirmed by the observation that oxidized LDL-induced lipid accumulation was attenuated in SIP-treated M2 macrophages. Furthermore, the atheroprotective effect of SIP was demonstrated by its anti-apoptotic effect on SIP-treated macrophages. The present study shows that SIP-induced M2 polarization of macrophages could be mediated via IL-4 signaling, and suggests that M2 polarization by SIP is responsible for the anti-atherogenic and atheroprotective properties of high-density lipoproteins in vivo. (C) 2014 Elsevier Inc. All rights reserved.