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Abstract
Background Mas is a newly discovered G protein-coupled receptor that plays a critical role in inflammatory responses. The gut-liver axis regulates neutrophilic inflammation, which is crucial in acute liver failure (ALF); however, the underlying mechanisms remain poorly understood. The aim of this study is to investigate Mas signaling and neutrophilic inflammation in ALF and to elucidate its underlying mechanisms.
Methods The 8-10 week-old male Mas1 -/-, Vil1 cre Mas1 f/f, and wild-type control mice were subjected to intraperitoneal challenge with D-galactosamine/lipopolysaccharide(D/L) for in vivo analysis of the gut-liver axis-dependent formation of neutrophil extracellular traps (NET), utilizing pharmacological compounds and genetic tools. Age-matched mice received injections of phosphate-buffered saline as vehicle controls.
Results The hepatic and ileal expression of Mas was significantly upregulated in ALF patients and mice models (IDDF2024-ABS-0338 Figure 1. The hepatic and ileal expression of Mas1 in D/L-induced ALF mice). The knockout of the Mas1 gene in both systemic and intestinal epithelial cells significantly alleviated D/L-induced NETosis and hepatotoxicity in mice (IDDF2024-ABS-0338 Figure 2. The knockout of the Mas1 gene in both systemic and intestinal epithelial cells significantly alleviated D/L-induced ALF in mice). The involvement of gut microbiota in the attenuated hepatotoxicity of Mas1 -/--D/L mice was confirmed through antibiotic experiments. The co-housed experiments between Mas1 -/- and WT mice have demonstrated that Mas1 -/- may confer protection by reducing the intestinal abundance of Eubacterium sp. and inhibiting deoxycholic acid (DCA) production (IDDF2024-ABS-0338 Figure 3. Mas1 may confer protection by reducing the intestinal abundance of Eubacterium sp and inhibiting DCA production). This was accompanied by hepatic activation of farnesoid X receptor (FXR) signaling and suppression of downstream sphingosine-1-phosphate (S1P)-dependent NETosis. As revealed by single-cell transcriptomics, the downregulation of NETosis in Mas1 -/--D/L mice was found to be dependent on the senescence of Cldn1+CD177+ neutrophils and the activation of Raf signaling (IDDF2024-ABS-0338 Figure 4. The downregulation of NETosis in Mas1Ko-D/L mice was found to be dependent on the senescence of Cldn1+CD177+ neutrophils and the activation of Raf signaling).
The hepatic and ileal expression of Mas1 in D/L-induced ALF mice
The knockout of the Mas1 gene in both systemic and intestinal epithelial cells significantly alleviated D/L-induced ALF in mice
Mas1 may confer protection by reducing the intestinal abundance of Eubacterium sp and inhibiting DCA production
The downregulation of NETosis in Mas1Ko-D/L mice was found to be dependent on the senescence of Cldn1+CD177+ neutrophils and the activation of Raf signaling
Conclusions Mas1 -/- significantly protects mice from D/L-induced hepatotoxicity by suppressing the FXR/S1P/Raf-dependent NETosis, thereby suggesting Mas as a promising therapeutic target for ALF.