Mas Signaling Potentiates Neutrophil Extracellular Traps Formation Induced by Endothelial Cells Derived S1P in Mice with Acute Liver Failure.

Mas, a newly identified G-protein-coupled receptor, is prevalent in myeloid-derived immune cells and plays a key role in inflammation. This study investigates Mas signaling and neutrophil extracellular traps (NETs) in acute liver failure (ALF), aiming to elucidate their mechanisms. Male Mas1(-/-) and wild-type mice, aged 6-8 weeks, receive intraperitoneally injected with lipopolysaccharide (LPS)/D-galactosamine (D-Gal) (L/G) to study NETs formation. Hepatic Mas expression increases in WT-L/G mice, whereas systemic Mas1 knockout significantly reduces L/G-induced NETs and hepatotoxicity. Antibiotics treatment and co-housing (Mas1(-/-)-L/G and WT-L/G mice) experiments show that gut flora influences the disease phenotype in Mas1(-/-)-L/G mice. Fecal metabolite analysis suggests that mice may be protected by reduced deoxycholic acid (DCA) production in Mas1(-/-) activated hepatic farnesoid X receptor (FXR), suppressing sphingosine-1-phosphate (S1P)-dependent NETs. Additionally, Mas1(-/-) also activates the FXR-S1P-NETs axis in the liver by inhibiting SHP2. Single-cell sequencing shows decreased interaction between endothelial cells and Cldn1(+)CD177(+) senescent neutrophils through Col4a1-CD44. This inhibits S1P-induced Raf signaling pathway activation and NETs formation. Mas signaling significantly impacts NETs formation, highlighting its potential as an anti-inflammatory therapeutic target for ALF.