Sphingosine-1-Phosphate and Macrophage Biology-How the Sphinx Tames the Big Eater

Abstract

The sphingolipid sphingosine-1-phosphate (S1P) is produced by sphingosine kinases to either signal through intracellular targets or to activate a family of specific G-protein-coupled receptors (S1PR). S1P levels are usually low in peripheral tissues compared to the vasculature, forming a gradient that mediates lymphocyte trafficking. However, S1P levels rise during inflammation in peripheral tissues, thereby affecting resident or recruited immune cells, including macrophages. As macrophages orchestrate initiation and resolution of inflammation, the sphingosine kinase/S1P/S1P-receptor axis emerges as an important determinant of macrophage function in the pathogenesis of inflammatory diseases such as cancer, atherosclerosis, and infection. In this review, we therefore summarize the current knowledge how S1P affects macrophage biology.

Keywords: atherosclerosis; cancer; infection; inflammation; macrophage polarization; macrophages; sphingosine-1-phosphate.

Figure 1

S1P signaling and macrophage function. The SPHK/S1P/S1PR axis regulates essential macrophage functions. Clockwise from upper left, S1PR1 signaling promotes macrophage migration, which is inhibited by S1PR2. Moreover, S1PR2 inhibits endotoxin-induced pyroptosis. Intracellular S1P produced by SPHK1 activates inflammatory pathways in macrophages, which are also activated downstream of S1PR2/3. S1PR1 mainly signals through STAT3 to induce cytokine production, but also induces expression of NLRP3. S1PR1 and S1PR2 are furthermore involved in the activation of the NLRP3 inflammasome trough divergent mechanisms. S1PR2 signaling promotes the opsonin-dependent uptake of the pathogenic fungus C. neoformans, but blocks uptake of bacteria such as E. coli. S1PR3 promotes bacterial killing via promoting ROS generation. SPHK1 is required for phagosome maturation, although it is unclear if S1PR signaling is involved in this process. Apoptotic cells release S1P to activate signaling through S1PR1, which promotes efferocytosis. In turn, S1PR5 blocks efferocytosis. S1PR4 is activated by apoptotic cell derived S1P to promote cytokine expression dependent on TRKA shuttling. AKT, protein kinase B; CASP, caspase; COX-2, cyclooxygenase-2; FcR, Fc receptor; IL, interleukin; MerTK, proto-oncogene tyrosine-protein kinase MER; NF-κB, nuclear factor “kappa-light-chain-enhancer” of activated B-cells; NGF, nerve growth factor; NLRP3, NACHT, LRR, and PYD domains-containing protein 3; P2X, P2X purinoceptor; RIP, receptor interacting protein; ROCK, rho-associated, coiled-coil-containing protein kinase; ROS, reactive oxygen species; S1P, sphingosine-1-phosphate; S1PR, sphingosine-1-phosphate receptor; SPHK, sphingosine kinase; STAT, signal transducer and activator of transcription; TLR, toll-like receptor; TNF, tumor necrosis factor; TNFR, TNF receptor; TRAF, TNF receptor-associated factor; TRKA, tropomyosin receptor kinase A.

Figure 2

S1P receptor signaling and macrophage function in disease. S1P is generated by the sequential breakdown of sphingomyelin and ceramide to sphingosine by sphingomyelinases and ceramidases, respectively, and the subsequent phosphorylation of sphingosine by sphingosine kinases. S1P is then degraded by S1P lyase or secreted from cells via the transporter SPNS2. Activation of S1P receptors on macrophages then triggers functional responses as indicated, whose targeting might be of interest in disease settings. Details can be found in the main text. BM, bone marrow; CDase, ceramidase; COPD, chronic obstructive pulmonary disease; MΦ, macrophage; S1P, sphingosine-1-phosphate; S1PR, sphingosine-1-phosphate receptor; SGPL1, S1P lyase; SMase, sphingomyelinase; SPHK, sphingosine kinase; SPNS2, Spinster homolog 2.