Treatment withβ-adrenoceptor agonist isoproterenol reduces non- parenchymal cell responses in LPS/D-Galn-induced liver injury

Abstract

Abstract Background and Aims There is growing evidence suggesting the involvement of sympathetic nervous system(SNS) in the development of liver disease. In order to gain a better understanding of the unknown mechanism by which the SNS reduces inflammatory harm through non-parenchymal liver cells(NPCs) during acute liver failure (ALF), we utilized isoproterenol (ISO), a beta-adrenoceptor agonist to mimic SNS signaling. Methods C57BL/6J mice were administered ISO in an ALF model established using LPS/D-GalN. Tandem mass tag(TMT) labeling proteomic analysis was employed to identify screen for differentially expressed proteins (DEPs). Results Pretreatment with ISO resulted in a reduction of LPS-stimulated inflammation signaling markers, speciallyMapk14 and NF-kB in human THP-1 cells. Additionally, ISO administration led to a decreasein serum levels of proinflammatory cytokines TNF-α, IL-1β, and IL-6 in ALF mice, thereby mitigating liver damage. Through TMT analysis, a total of 1587 differentially expressed proteins (DEPs) were identified in isolated NPCs. Notably, over 60% of the DEPs observed in the ISO vs. ALF comparison were also found in the Con vs. ALF comparison. Enrichment analysis revealed that the DEPs influenced by ISO treatment were associated with heme and fatty acid metabolism, interferon gamma response, TNFA signaling pathway and mitochondrial oxidation function. PPI network analysis indicated Mapk14 and Caspase3 signaling may serve as potentially valuable indicators of ISO intervention. Specifically, the markers on activate macrophages were identified downregulated in ISO initiation, such as Mapk14, Casp1, Casp8, and Mrc1. ISO treatment increased the abundance of anti-inflammatory markers in macrophages, as evidenced by the immunohistochemistry(IHC) slides showing an increase in Arg+ staining, and a reduction in iNOS+ cell infiltration. Conclusion Prior treatment with ISO could potentially modulate the biological functions of NPCs and may serve as an innovative pharmacotherapy for the purpose of delaying the pathogenesis and progression of ALF.