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.
Highlights
In 1887, Metchnikoff published work on the nature host cells combating bacterial infection
Initial studies in human alveolar macrophages suggested that S1P alone induced NADPH-oxidase (NOX)2-dependent production of ROS [126] to promote IL-1β and tumor necrosis factor-α (TNF-α) production by murine peritoneal macrophages [127]. These findings were recently supported by a study suggesting that S1P stimulation of murine bone marrow-derived macrophages (BMDM) triggered the expression of inflammatory markers including TNF-α, CCL2, and inducible NO-synthase, which were suppressed by targeting S1PR2/3 and downstream c-Jun N-terminal kinase (JNK) activation, again exemplifying the cooperate potential of S1PR2/3 signaling in macrophages [128]
We previously showed that S1P is released by apoptotic breast cancer cells and polarizes macrophages toward a M2-like phenotype, characterized by reduced TNF-α, IL-12 but increased IL8 and IL-10 secretion [138]
Summary
In 1887, Metchnikoff published work on the nature host cells combating bacterial infection. Since macrophages are the most plastic cells of the immune system, contradictory studies on macrophage-specific S1P receptor functions are most likely due to different S1PR expression profiles, sources and distinct in vitro macrophage differentiation protocols. This may be explained by divergent functions of SPHK isoforms in inflammation, as has been noted in a model of inflammation-induced colon cancer, where SPHK2 ablation triggered SPHK1-dependent cytokine production in myeloid cells and promoted M1 macrophage activation [124].
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