Sphingosine-1-phosphate receptor 4 (S1PR4) (S1PR4)

Sphingosine-1-phosphate receptor 4 (S1PR4) is a G protein-coupled receptor that belongs to the lysophospholipid receptor family and is primarily expressed in lymphoid and hematopoietic tissues, such as the spleen, lymph nodes, and bone marrow [10, 12]. It signals through Gi, Go, and G12/13 pathways to regulate critical processes including immune cell activation, cytokine production, and megakaryocyte differentiation [4, 5, 6]. Unlike S1PR1, which primarily drives lymphocyte egress, S1PR4 modulates the activation of myeloid cells like macrophages and dendritic cells, influencing the inflammatory milieu [1, 2]. S1PR4 is implicated in various diseases, including chronic inflammatory conditions like asthma and colitis, autoimmune disorders, and several types of cancer where it affects tumor immunity and progression [2, 11, 13]. It also plays a significant role in the pathogenesis of nonalcoholic steatohepatitis (NASH) by promoting NLRP3 inflammasome activation in hepatic macrophages [14, 15]. Pharmacological targeting of S1PR4 is achieved by multi-receptor modulators such as etrasimod and fingolimod, which are used to treat ulcerative colitis and multiple sclerosis, respectively [3, 5, 9]. Selective S1PR4 ligands are currently being explored as potential therapeutic agents for more targeted immunomodulation and cancer therapy [3, 4].

Other names

S1P4EDG6LPC1Endothelial differentiation G-protein-coupled receptor 6Sphingosine 1-phosphate receptor Edg-6

S1PR4 modulators typically act as agonists or functional antagonists that induce receptor internalization and degradation, thereby inhibiting downstream signaling pathways such as ERK/MAPK and PLC, and modulating the production of pro-inflammatory cytokines like IL-17 and IFN-alpha [3, 5, 9].