Figure 1.

Role of S1P/S1PRs in macrophages. S1PRs on macrophages can be activated by extracellular molecules such as cytokines, chemokines, or growth factors. Receptor activation transmits a signal for sphingomyelinase (SMase) and ceramidase (CDase) to sequentially breakdown sphingomyelin and ceramide, respectively, to generate sphingosine. Phosphorylation (p) of the latter by Sphk1 produces S1P, which induces intracellular signaling to activate kinase-mediated phosphorylation of SphK1. Translocation of S1P from the cytosol to the cell membrane also leads to phosphorylation of sphingosine to S1P. SphK1 is essential for the TNF signaling pathway for downstream molecule NF-κB activation. Akt signaling molecules are activated by S1P₁ and S1P₄ and signal for macrophage activity and survival such as MCP-1 and MIP-1α. G protein through Rac1 and RhoA activation plays a role in S1P₁ and S1P₃ as the regulators of macrophage migration and infiltration. To the contrary, the migration signals are inhibited by S1P₂, by which NLRP3 becomes a considerable signal to shade the S1P₂ blockade mechanism to inhibit the macrophage death signal, caspase-11. Meanwhile, S1P₅ signal activation regulates monocytes migration activity together with CCR2. TGF- β signaling pathway through molecules downstream of Smad3, Akt, and mTOR Smad3 mediates HIF-1α stabilization, and expression thus activates targeting genes containing HRE.