A novel S1PR4 functional antagonist prevents nonalcoholic steatohepatitis by deactivating the NLRP3 inflammasome without causing lymphopenia

Abstract

Sphingosine 1-phosphate (S1P) receptors (S1PRs) are a group of G protein-coupled receptors that confer a broad range of functional effects in chronic inflammatory diseases and metabolic diseases. S1PRs may also be involved in the development of non-alcoholic steatohepatitis (NASH), but the specific subtypes involved and the mechanism of action are unclear. Here we show that the livers of various mouse models of NASH as well as Kupffer cells had a particularly strong expression of S1pr4. Accordingly, genetic depletion of S1pr4 protected the mice against hepatic inflammation and fibrosis. Moreover, SLB736, a novel selective functional antagonist of SIPR4 prevented diet-induced NASH in mice without lymphopenia. S1P increased the expression of S1pr4 in Kupffer cells and activated the NLRP3 inflammasome through PLC/IP3/IP3R-dependent [Ca++] signaling. SLB736 treatment or S1pr4 depletion in Kupffer cells inhibited LPS-mediated Ca++ release and deactivated the NLRP3 inflammasome. S1PR4 antagonism may be a novel therapeutic strategy for NASH.

Novel functions of S1P in chronic itchy and inflammatory skin diseases

“…Whilst S1PR5 inhibits the ERK and AC pathways and also activates PI3K, S1PR4 is thought to activate ERK and possibly PLC. 11,18,31,32 Whilst S1PR4 signalling influences the production of cytokines from T-cells, chemotaxis and the differentiation of dendritic cells, the physiologic effects of S1PR5 signalling are not as clear, though research suggests that it may play a role in myelination, NK cell homing to inflamed organs and endothelial tight-junction function in the nervous system. 30,[33][34][35][36][37] Signalling pathways of the five S1PRs are visualized in Figure 2.…”