Cholinergic Anti-inflammatory Pathway Attenuates Acute Liver Failure Through Inhibiting MAdCAM1/α4β7-mediated Gut-derived Proinflammatory Lymphocytes Accumulation.
Cholinergic Anti-inflammatory Pathway Attenuates Acute Liver Failure Through Inhibiting MAdCAM1/α4β7-mediated Gut-derived Proinflammatory Lymphocytes Accumulation.
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DOI：
10.1016/j.jcmgh.2023.10.012
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发表时间：
2024
影响因子：
7.2
通讯作者：
Liu, Jinfeng
中科院分区：
文献类型：
--
作者：
Fu, Shan;Ni, Tianzhi;Zhang, Mengmeng;Ren, Danfeng;Feng, Yali;Yao, Naijuan;Zhang, Xiaoli;Wang, Ruojing;Xu, Weicheng;Yang, Nan;Yang, Yuan;He, Yingli;Zhao, Yingren;Liu, Jinfeng
关键词：
胆碱能抗炎通路（CAP）在急性肝衰竭（ALF）炎症风暴中的作用尚不明确。肝-肠轴已被证明对肝脏的稳态至关重要。研究CAP对肝-肠轴的调节作用将有助于我们对胆碱能抗炎机制的理解。采用脂多糖和D-氨基半乳糖联合注射建立ALF模型。PNU-282987用于激活CAP。进行组织学染色、实时聚合酶链反应、蛋白质印迹、RNA测序和流式细胞术。还分析了来自肝衰竭患者的肝活检标本和患者血清。我们证实激活CAP减轻了肝细胞破坏，伴随着肝细胞凋亡、促炎细胞因子和NLRP 3炎性体激活的显著减少。此外，ALF可诱导肝脏MAdCAM 1和血清MAdCAM 1水平升高，且MAdCAM 1水平与肝损伤程度和促炎标志物表达呈正相关。此外，激活CAP主要下调MAdCAM 1在内皮细胞上的异位表达，抑制NF-κB p65核转位部分归因于MAdCAM 1的减少。值得注意的是，在ALF中，MAdCAM 1的异常肝脏表达随后将肠道来源的α4β7+ CD 4 +T细胞募集到肝脏，其表现出增强的IFN-γ分泌和IL-17产生表型。最后，我们发现，血清和肝脏MAdCAM 1水平升高，肝衰竭患者的临床进程密切相关。在患者中也证实了β7+细胞的肝浸润增加。激活CAP可通过抑制MAdCAM 1/α4β7介导的肠源性促炎淋巴细胞浸润减轻肝损伤，为ALF提供了潜在的治疗靶点。
The function of cholinergic anti-inflammatory pathway (CAP) in acute liver failure (ALF) with inflammatory storm remains indefinite. The liver-gut axis has been proved to be crucial for liver homeostasis. Investigation about CAP regulation on liver-gut axis would enrich our understanding over cholinergic anti-inflammatory mechanism. Co-injection of lipopolysaccharide and D-galactosamine was used to establish the model of ALF. PNU-282987 was used to activate the CAP. Histological staining, real-time polymerase chain reaction, Western blotting, RNA sequencing, and flow cytometry were conducted. Liver biopsy specimens and patients’ serum from patients with liver failure were also analyzed. We confirmed that activating the CAP alleviated hepatocyte destruction, accompanied by a significant decrease in hepatocyte apoptosis, pro-inflammatory cytokines, and NLRP3 inflammasome activation. Moreover, hepatic MAdCAM1 and serum MAdCAM1 levels were induced in ALF, and MAdCAM1 levels were positively correlated with the extent of liver damage and the expression of pro-inflammatory markers. Furthermore, activating the CAP mainly downregulated ectopic expression of MAdCAM1 on endothelial cells, and inhibition of NF-κB p65 nuclear translocation was partly attributed to the decreased MAdCAM1. Notably, in ALF, the aberrant hepatic expression of MAdCAM1 subsequently recruited gut-derived α4β7+ CD4+T cells to the liver, which exhibited an augmented IFN-γ-secreting and IL-17-producing phenotype. Finally, we revealed that the levels of serum and hepatic MAdCAM1 were elevated in patients with liver failure and closely correlated with clinical course. Increasing hepatic infiltration of β7+ cells were also confirmed in patients. Activating the CAP attenuated liver injury by inhibiting MAdCAM1/α4β7 -mediated gut-derived proinflammatory lymphocytes infiltration, which provides a potential therapeutic target for ALF.
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影响因子：
13.5
作者：
Liaskou, Evaggelia;Karikoski, Marika;Reynolds, Gary M.;Lalor, Patricia F.;Weston, Chris J.;Pullen, Nick;Salmi, Marko;Jalkanen, Sirpa;Adams, David H.
通讯作者：
Adams, David H.
影响因子：
25.7
作者：
通讯作者：
--
影响因子：
5.5
作者：
Chatterjee, Prodyot K.;Al-Abed, Yousef;Metz, Christine N.
通讯作者：
Metz, Christine N.
DOI：
10.1002/hep.32193
发表时间：
2022-03
期刊：
Hepatology (Baltimore, Md.)
影响因子：
--
作者：
Graham JJ;Mukherjee S;Yuksel M;Sanabria Mateos R;Si T;Huang Z;Huang X;Abu Arqoub H;Patel V;McPhail M;Zen Y;Heaton N;Longhi MS;Heneghan MA;Liberal R;Vergani D;Mieli-Vergani G;Ma Y;Hayee B
通讯作者：
Hayee B
影响因子：
37.8
作者：
Guarini, S;Altavilla, D;Squadrito, F
通讯作者：
Squadrito, F