Sphingosine 1-Phosphate Receptor 4 Promotes Nonalcoholic Steatohepatitis by Activating NLRP3 Inflammasome

Abstract

Background & Aims Sphingosine 1-phosphate receptors (S1PRs) are a group of G-protein–coupled receptors that confer a broad range of functional effects in chronic inflammatory and metabolic diseases. S1PRs also may mediate the development of nonalcoholic steatohepatitis (NASH), but the specific subtypes involved and the mechanism of action are unclear. Methods We investigated which type of S1PR isoforms is activated in various murine models of NASH. The mechanism of action of S1PR4 was examined in hepatic macrophages isolated from high-fat, high-cholesterol diet (HFHCD)-fed mice. We developed a selective S1PR4 functional antagonist by screening the fingolimod (2-amino-2-[2-(4- n -octylphenyl)ethyl]-1,3- propanediol hydrochloride)-like sphingolipid-focused library. Results The livers of various mouse models of NASH as well as hepatic macrophages showed high expression of S1pr4 . Moreover, in a cohort of NASH patients, expression of S1PR4 was 6-fold higher than those of healthy controls. S1pr4 +/- mice were protected from HFHCD-induced NASH and hepatic fibrosis without changes in steatosis. S1pr4 depletion in hepatic macrophages inhibited lipopolysaccharide-mediated Ca ++ release and deactivated the Nod-like receptor pyrin domain-containning protein 3 (NLRP3) inflammasome. S1P increased the expression of S1pr4 in hepatic macrophages and activated NLRP3 inflammasome through inositol trisphosphate/inositol trisphosphate–receptor–dependent [Ca ++ ] signaling. To further clarify the biological function of S1PR4, we developed SLB736, a novel selective functional antagonist of SIPR4. Similar to S1pr4 +/- mice, administration of SLB736 to HFHCD-fed mice prevented the development of NASH and hepatic fibrosis, but not steatosis, by deactivating the NLRP3 inflammasome. Conclusions S1PR4 may be a new therapeutic target for NASH that mediates the activation of NLRP3 inflammasome in hepatic macrophages.

Sphingosine-1-Phosphate Alleviates Irradiation Induced Salivary Gland Hypofunction through Preserving Endothelial Cells and Resident Macrophages

“…Smpd1 and Smpd2 are most abundant in the Endo cluster, Sphk1 and Sphk2 are widely expressed in most types of cells, while all detectable ceramidases ( Acer2/3 and Asah1/2 ) and the S1P transporters Spns2 are enriched in the Endo cluster and resident macrophages (rMφs), suggesting that they are the main sources of extracellular S1P in mouse SMGs ( Figure 4 A–C). Notably, among the five S1P receptors, S1pr1 and S1pr5 signaling showed anti-inflammatory, vascular protective, and pro-regenerative effects [ 37 , 38 , 39 ], whereas S1pr2, S1pr3, and S1pr4 signaling pathways are reported to be pro-inflammatory and pro-fibrotic [ 40 , 41 , 42 ]. S1pr1 mRNA was enriched in the Endo cluster and present in multiple types of cells, including resident macrophages; S1pr2 mRNA was present in macrophages and ductal cells, while S1pr3/4/5 mRNAs were enriched in lymphocytes such as innate lymphoid cells (ILCs) and NKT cells ( Figure 4 A–C).…”

Hepatic Stellate Cells: Dictating Outcome in Nonalcoholic Fatty Liver Disease

“… 108 In addition to promoting hepatic stellate cell activation, sphingosine-1-phosphate can also directly act on immune cells, such as macrophages, to promote NASH pathogenesis. 126 In a rodent model of diet-induced NASH, genetic or pharmacologic inhibition of the sphingosine-1-phosphate receptor 4 significantly reduces inflammation and NASH fibrosis via mechanisms involving NLR family pyrin domain containing 3 (NLRP3) inflammasome activation in macrophages. 126 …”

“… 126 In a rodent model of diet-induced NASH, genetic or pharmacologic inhibition of the sphingosine-1-phosphate receptor 4 significantly reduces inflammation and NASH fibrosis via mechanisms involving NLR family pyrin domain containing 3 (NLRP3) inflammasome activation in macrophages. 126 …”

GPCRs and fibroblast heterogeneity in fibroblast‐associated diseases

“…Also inhibits collagen synthesis, proliferation, and transdifferentiation of HSCs a [108] Endothelin receptor type B (ETBR) G s , G i , G q Upregulated in fibrotic condition and activation increases HSC contraction. The interplay of ETRs in the condition warrants exploration [109] Sphingosine-1-phosphate receptor 1 (S1PR1) G i Leads to differentiation of bone marrow mesenchymal stem cells (BMSCs) to myofibroblasts, mediating liver fibrogenesis [110] Sphingosine-1-phosphate receptor 2 (S1PR2) G i , G q , G 12/13 Promotes neutrophil activation and inflammation. Also, macrophage S1PR2 in the liver upregulates NLRP3 inflammasome inducing fibrogenesis [110,111] Sphingosine-1-phosphate receptor 3 (S1PR3) G i , G q , G 12/13 Mediates bone marrow monocyte (BMM) motility and their activation fostering hepatic fibrosis [110] Sphingosine-1-phosphate receptor 4 (S1PR4) G i Activation of NLRP3 inflammasome in hepatic macrophages stimulates the development of liver fibrosis [110] Cannabinoid receptor 1 (CB1) G i Mediates HSC proliferation and is positively correlated to the expression of fibrosis-mediated genes ACTA2, TIMP-1, and MMP-13 a…”