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

Abstract

Abstract 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.

Keywords

• Mas
• sphingosine 1‐phosphate
• neutrophil extracellular traps
• farnesoid X receptor
• endothelial cells