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Interleukin-22 ameliorates acute-on-chronic liver failure by reprogramming of impaired regeneration pathways in mice
Journal of Hepatology ( IF 25.7 ) Pub Date : 2020-04-01 , DOI: 10.1016/j.jhep.2019.11.013
Xiaogang Xiang 1 , Dechun Feng 2 , Seonghwan Hwang 2 , Tianyi Ren 2 , Xiaolin Wang 2 , Eszter Trojnar 3 , Csaba Matyas 3 , Ruidong Mo 4 , Dabao Shang 4 , Yong He 2 , Wonhyo Seo 2 , Vijay H Shah 5 , Pal Pacher 3 , Qing Xie 4 , Bin Gao 2
Affiliation  

BACKGROUND & AIMS Acute-on-chronic liver failure (ACLF) is a clinical syndrome defined by liver failure on preexisting chronic liver disease and is often associated with bacterial infection with high short-term mortality. Experimental models that fully reproduce ACLF and effective pharmacological therapies are lacking. METHODS To mimic ACLF conditions, we developed a severe liver injury model by combining chronic injury (chronic carbon tetrachloride [CCl4] injection), acute hepatic insult (injection of a double dose CCl4), and bacterial infection (intraperitoneal injection of bacteria). Serum and liver samples from patients with ACLF or acute drug-induced liver injury (DILI) were used. Liver injury and regeneration were assessed to ascertain for potential benefits of interleukin-22 (IL-22Fc) administration. RESULTS This severe liver injury model developed acute-on-chronic liver injury, bacterial infection, multi-organ injury, and high mortality, recapitulating some features of clinical ACLF. Liver regeneration in this model was severely impaired due to the shift from the activation of pro-regenerative IL-6/STAT3 to anti-regenerative IFN-γ/STAT1 pathway. The impaired IL-6/STAT3 activation was due to Kupffer cell inability to produce IL-6; whereas the enhanced STAT1 activation was due to strong innate immune response and subsequent production of IFN-γ. Compared to DILI patients, ACLF patients had higher levels of IFN-γ but lower liver regeneration. IL-22Fc treatment improved survival of the ACLF mice by reversing the STAT1/STAT3 pathway imbalance and enhancing expression of many anti-bacterial genes in a manner involving the anti-apoptotic protein BCL2. CONCLUSIONS Acute-on-chronic liver injury or bacterial infection is associated with impaired liver regeneration due to a shift from the pro-regenerative to anti-regenerative pathways, IL-22Fc therapy reverses this shift and attenuates bacterial infection, thus IL-22Fc may have therapeutic potential for ACLF treatment.

中文翻译:

Interleukin-22 通过重编程小鼠受损的再生途径改善急性慢性肝衰竭

背景和目的 急性慢性肝衰竭 (ACLF) 是一种临床综合征,定义为既往存在慢性肝病的肝衰竭,通常与细菌感染相关,短期死亡率高。缺乏完全重现 ACLF 和有效药物疗法的实验模型。方法 为了模拟 ACLF 条件,我们通过结合慢性损伤(慢性四氯化碳 [CCl4] 注射)、急性肝损伤(注射双剂量 CCl4)和细菌感染(腹腔注射细菌)开发了严重肝损伤模型。使用来自 ACLF 或急性药物性肝损伤 (DILI) 患者的血清和肝脏样本。评估肝损伤和再生以确定白细胞介素 22 (IL-22Fc) 给药的潜在益处。结果 这种严重肝损伤模型发展为急性-慢性肝损伤、细菌感染、多器官损伤和高死亡率,概括了临床 ACLF 的一些特征。由于从促再生 IL-6/STAT3 激活到抗再生 IFN-γ/STAT1 通路的转变,该模型中的肝脏再生受到严重损害。IL-6/STAT3 活化受损是由于库普弗细胞不能产生 IL-6;而增强的 STAT1 激活是由于强烈的先天免疫反应和随后产生的 IFN-γ。与 DILI 患者相比,ACLF 患者的 IFN-γ 水平较高,但肝再生水平较低。IL-22Fc 治疗通过逆转 STAT1/STAT3 途径失衡并以涉及抗凋亡蛋白 BCL2 的方式增强许多抗菌基因的表达,从而提高了 ACLF 小鼠的存活率。结论 急性慢性肝损伤或细菌感染与肝再生受损有关,因为从促再生途径到抗再生途径的转变,IL-22Fc 治疗逆转了这种转变并减轻了细菌感染,因此 IL-22Fc 可能具有ACLF 治疗的治疗潜力。
更新日期:2020-04-01
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