Treatment with β-Adrenoceptor Agonist Isoproterenol Reduces Non-parenchymal Cell Responses in LPS/D-GalN-Induced Liver Injury
Treatment with β-Adrenoceptor Agonist Isoproterenol Reduces Non-parenchymal Cell Responses in LPS/D-GalN-Induced Liver Injury
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DOI：
10.1007/s10753-023-01941-z
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发表时间：
2023-12-21
期刊：
影响因子：
5.1
通讯作者：
Liu，Jinfeng
中科院分区：
文献类型：
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作者：
Wu，Yuchao;Ni，Tianzhi;Liu，Jinfeng
越来越多的证据表明交感神经系统（SNS）参与肝病的发展。为了广泛了解SNS在急性肝衰竭（ALF）期间加重非实质肝细胞（NPC）炎症损伤的模糊过程，我们采用β-肾上腺素受体激动剂异丙肾上腺素（ISO）来模拟SNS信号。采用LPS/D-GalN建立C57 BL/6 J小鼠急性肝衰竭（ALF）模型，即ISO + ALF模型。从肝组织中分离非实质细胞（NPC），并消化用于串联质量标签（TMT）标记的蛋白质组学以鉴定差异表达的蛋白质（DEP）。ISO的施用导致促炎细胞因子的血清水平降低，TNF-α、IL-1β和IL-6，减轻肝损伤。通过TMT分析，可以在分离的NPC中鉴定出1587个差异表达蛋白（DEPs）。值得注意的是，ISO + ALFvs.ALF比较中超过60%的DEP在Convs.ALF比较中共享。根据富集分析，ISO影响ALF小鼠的DEPs与血红素和脂肪酸代谢、干扰素γ反应、TNFA信号通路和线粒体氧化功能的生物学功能有关。蛋白质-蛋白质相互作用网络分析表明，Mapk 14和Caspase 3可能是ISO干预的潜在有价值的指标。此外，激活的巨噬细胞上的标记物，如Mapk 14，Casp 1，Casp 8和Mrc 1，在ISO启动后被鉴定为下调。ISO处理增加了小鼠巨噬细胞中抗炎标志物的丰度，如免疫组织化学（IHC）载玻片所示，其显示Arg +染色增加和iNOS +染色减少。此外，ISO预处理还导致LPS刺激的炎症信号标志物Mapk 14和NF-κB在人THP-1细胞中的减少。ISO的预先治疗可能有可能改变NPC的生物学功能，并可作为延迟ALF发病机制和进展的创新药物治疗。
There is an increasing evidence indicating the involvement of the sympathetic nervous system (SNS) in liver disease development. To achieve an extensive comprehension of the obscure process by which the SNS alleviates inflammatory damage in non-parenchymal liver cells (NPCs) during acute liver failure (ALF), we employ isoproterenol (ISO), a beta-adrenoceptor agonist, to mimic SNS signaling. ISO was administered to C57BL/6J mice to establish an acute liver failure (ALF) model using LPS/D-GalN, which was defined as ISO + ALF. Non-parenchymal cells (NPCs) were isolated from liver tissues and digested for tandem mass tag (TMT) labeled proteomics to identify differentially expressed proteins (DEPs). The administration of ISO resulted in a decreased serum levels of pro-inflammatory cytokines,e.g., TNF-α, IL-1β, and IL-6 in ALF mice, which alleviated liver damage. By using TMT analysis, it was possible to identify 1587 differentially expressed proteins (DEPs) in isolated NPCs. Notably, over 60% of the DEPs in the ISO + ALFvs.ALF comparison were shared in the Convs.ALF comparison. According to enrichment analysis, the DEPs influenced by ISO in ALF mice were linked to biological functions of heme and fatty acid metabolism, interferon gamma response, TNFA signaling pathway, and mitochondrial oxidation function. Protein-protein interaction network analysis indicated Mapk14 and Caspase3 may serve as potentially valuable indicators of ISO intervention. In addition, the markers on activated macrophages, such as Mapk14, Casp1, Casp8, and Mrc1, were identified downregulated after ISO initiation. ISO treatment increased the abundance of anti-inflammatory markers in mouse macrophages, as evidenced by the immunohistochemistry (IHC) slides showing an increase in Arg + staining and a reduction in iNOS + staining. Furthermore, pretreatment with ISO also resulted in a reduction of LPS-stimulated inflammation signaling markers, Mapk14 and NF-κB, in human THP-1 cells. Prior treatment with ISO may have the potential to modify the biological functions of NPCs and could serve as an innovative pharmacotherapy for delaying the pathogenesis and progression of ALF.