当前位置: X-MOL 学术J. Hepatol. › 论文详情
Our official English website, www.x-mol.net, welcomes your feedback! (Note: you will need to create a separate account there.)
Hepatocyte-specific deletion of IL1-RI attenuates liver injury by blocking IL-1 driven autoinflammation
Journal of Hepatology ( IF 25.7 ) Pub Date : 2018-05-01 , DOI: 10.1016/j.jhep.2018.01.008
Nadine Gehrke , Nadine Hövelmeyer , Ari Waisman , Beate K. Straub , Julia Weinmann-Menke , Marcus A. Wörns , Peter R. Galle , Jörn M. Schattenberg

BACKGROUND & AIMS Interleukin (IL)-1-type cytokines including IL-1α, IL-1β and interleukin-1 receptor antagonist (IL-1Ra) are among the most potent molecules of the innate immune system and exert biological activities through the ubiquitously expressed interleukin-1 receptor type 1 (IL-1R1). The role of IL-1R1 in hepatocytes during acute liver failure (ALF) remains undetermined. METHODS The role of IL-1R1 during ALF was investigated using a novel transgenic mouse model exhibiting deletion of all signaling-capable IL-1R isoforms in hepatocytes (Il1r1Hep-/-). RESULTS ALF induced by D-galactosamine (D-GalN) and lipopolysaccharide (LPS) was significantly attenuated in Il1r1Hep-/- mice leading to reduced mortality. Conditional deletion of Il1r1 decreased activation of injurious c-Jun N-terminal kinases (JNK)/c-Jun signaling, activated nuclear factor-kappa B (NF-κB) p65, inhibited extracellular signal-regulated kinase (ERK) and prevented caspase 3-mediated apoptosis. Moreover, Il1r1Hep-/- mice exhibited reduced local and systemic inflammatory cytokine and chemokine levels, especially TNF-α, IL-1α/β, IL-6, CC-chemokine ligand 2 (CCL2), C-X-C motif ligand 1 (CXCL-1) and CXCL-2, and a reduced neutrophil recruitment into the hepatic tissue in response to injury. NLRP3 inflammasome expression and caspase 1 activation were suppressed in the absence of the hepatocellular IL-1R1. Inhibition of IL-1R1 using IL-1ra (anakinra) attenuated the severity of liver injury, while IL-1α administration exaggerated it. These effects were lost ex vivo and at later time points, supporting a role of IL-1R1 in inflammatory signal amplification during acute liver injury. CONCLUSION IL-1R1 in hepatocytes plays a pivotal role in an IL-1-driven auto-amplification of cell death and inflammation in the onset of ALF. LAY SUMMARY Acute liver injury which can cause lethal liver failure is medicated by a class of proteins called cytokines. Among these, interleukin-1 (IL-1) and the corresponding receptor IL-1R1 play a prominent role in the immune system, but their role in the liver is undetermined. In the current study, a novel mouse model with defective IL-1R1 in liver cells was studied. Mice lacking this receptor in liver cells were protected from cell death to a certain extent. This protection occurred only in the presence of other, neighboring cells, arguing for the involvement of proteins derived from these cells. This effect is called paracrine signaling and the current study has for the first time shown that the IL-1R1 receptor on hepatocytes is involved in acute liver failure in this context. The approved drug anakinra - which blocks IL-1R1 - had the same effect, supporting the proposed mechanism of action. The findings of this study suggest new treatment options for patients with acute liver failure by blocking defined signals of the immune system.

中文翻译:

IL1-RI 的肝细胞特异性缺失通过阻断 IL-1 驱动的自身炎症减轻肝损伤

背景与目的 白介素 (IL)-1 型细胞因子包括 IL-1α、IL-1β 和白介素 1 受体拮抗剂 (IL-1Ra) 是先天免疫系统中最有效的分子之一,并通过无处不在的表达来发挥生物活性。白细胞介素 1 受体 1 型 (IL-1R1)。IL-1R1 在急性肝衰竭 (ALF) 期间肝细胞中的作用仍未确定。方法 使用一种新型转基因小鼠模型研究 IL-1R1 在 ALF 中的作用,该模型表现出肝细胞中所有具有信号传导能力的 IL-1R 异构体 (Il1r1Hep-/-) 的缺失。结果 由 D-半乳糖胺 (D-GalN) 和脂多糖 (LPS) 诱导的 ALF 在 Il1r1Hep-/- 小鼠中显着减弱,导致死亡率降低。Il1r1 的条件性缺失降低了有害 c-Jun N 端激酶 (JNK)/c-Jun 信号传导的激活,激活核因子-κB (NF-κB) p65,抑制细胞外信号调节激酶 (ERK) 并阻止半胱天冬酶 3 介导的细胞凋亡。此外,Il1r1Hep-/- 小鼠的局部和全身炎症细胞因子和趋化因子水平降低,尤其是 TNF-α、IL-1α/β、IL-6、CC-趋化因子配体 2(CCL2)、CXC 基序配体 1(CXCL-1 ) 和 CXCL-2,以及减少中性粒细胞募集到肝组织以应对损伤。在缺乏肝细胞 IL-1R1 的情况下,NLRP3 炎性体表达和半胱天冬酶 1 激活受到抑制。使用 IL-1ra(阿那白滞素)抑制 IL-1R1 可减轻肝损伤的严重程度,而 IL-1α 给药则夸大了它。这些作用在离体和稍后的时间点消失,支持 IL-1R1 在急性肝损伤期间炎症信号放大中的作用。结论 肝细胞中的 IL-1R1 在 ALF 发作时 IL-1 驱动的细胞死亡和炎症的自动扩增中起关键作用。概述 可导致致命肝功能衰竭的急性肝损伤由一类称为细胞因子的蛋白质治疗。其中,白细胞介素-1(IL-1)和相应的受体 IL-1R1 在免疫系统中发挥着突出的作用,但它们在肝脏中的作用尚未确定。在目前的研究中,研究了肝细胞中 IL-1R1 缺陷的新型小鼠模型。肝细胞中缺乏这种受体的小鼠在一定程度上可以免于细胞死亡。这种保护仅在其他相邻细胞存在的情况下发生,这证明了源自这些细胞的蛋白质的参与。这种效应称为旁分泌信号传导,目前的研究首次表明肝细胞上的 IL-1R1 受体与这种情况下的急性肝衰竭有关。批准的药物阿那白滞素(阻断 IL-1R1)具有相同的效果,支持拟议的作用机制。这项研究的结果通过阻断免疫系统的明确信号为急性肝衰竭患者提供了新的治疗选择。
更新日期:2018-05-01
down
wechat
bug