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.