Beyond Immune Cell Migration: The Emerging Role of the Sphingosine-1-phosphate Receptor S1PR4 as a Modulator of Innate Immune Cell Activation

Figure 2

Impact of S1PR4 on immune cell activation, trafficking, and differentiation. (1) S1P triggers the S1PR4-dependent production of IL-27 by human DCs, which enables Tregs to efficiently suppress cytotoxic CD8⁺ T cells. (2) S1PR4 activation induces translocation of TRKA to the cell surface to enable the production of tumor-promoting cytokines (IL-6, IL-10) by macrophages. (3) S1PR4 activation preserves surface expression of the human pDC-specific inhibitory receptor ILT7 leading to decreased DAMP-induced IFN-α secretion and reduced cytotoxic T cell activation by human pDCs. (4) Enhanced S1PR4-dependent IL-17 production increases neutrophil numbers in blood, liver, and lung of mice putatively by enhancing granulopoiesis. (5) Activation of S1PR4 on neutrophils enhances neutrophil trafficking from the inflamed tissue to the draining lymph node. (6) Activation of S1PR4 on DCs leads to an enrichment of DCs in lymph nodes among others regulated by CCL19 and CCL21 through CCR7. (7) S1PR4 on CDPs within the bone marrow stimulates their trafficking towards well-perfused areas following the S1P gradient, where they differentiate to pDCs under the influence of FLT3-L. (8) S1PR4 signaling during megakaryocyte development promotes their differentiation and the formation of platelets accompanied by the upregulation of megakaryocyte and platelet markers such as CD41 and the platelet-specific receptor P2Y12. DAMP: danger-associated molecular pattern; DC: dendritic cell; FLT3-L: fms-like tyrosine kinase 3-ligand; ILT7: inhibitory receptor Ig-like transcript 7; pDC: plasmacytoid DC; TRKA: tropomyosin receptor kinase A.