Interleukin-6 Trans Signaling Regulates Neutrophilic Inflammation in Alcohol-Associated Hepatitis.

IF 4.7 2区 医学 Q1 PATHOLOGY
Gaurav Sarode, Ming-Fo Hsu, Fawaz G Haj, Sergio Barace, Josepmaria Argemi, Mengfei Liu, Prisha Pandita, Sheng Cao, Vijay H Shah, Dorina Gui, Ramon Bataller, Vikrant Rachakonda
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Abstract

Alcohol-associated hepatitis (AH) is a form of acute on chronic liver failure characterized by intrahepatic neutrophilic inflammation. In hepatocytes, IL-6 can signal through membrane-bound (classical signaling) or soluble (trans signaling) IL-6 receptors to regulate liver injury responses. The goal of this study was to determine the role of IL-6 trans signaling in the pathophysiology of AH. Liver RNA-Seq from alcohol-related liver disease patients demonstrated declining IL-6 receptor (IL-6R) expression with increasing AH severity, and TGF-β1 was the strongest negative regulator of IL-6R expression; however, STAT3-dependent gene expression increased in severe AH. In vitro, HepG2 cells were exposed to TGF-β1 to inhibit IL-6R expression, followed by STAT3 activation with 1) IL-6 to stimulate classical signaling or 2) hyper-IL-6, a recombinant IL-6/IL-6Rα peptide, to activate trans signaling. Only hyper-IL-6, but not IL-6, restored STAT3 activation in the face of suppressed IL-6R. RNA-Seq was performed on hyper-IL-6-stimulated cells, yielding a gene signature identifying a subset of AH patients with 1) enhanced IL-6TS activity 2) increased intrahepatic neutrophilic infiltration and 3) transcriptional enrichment of leukocyte migration pathways. Female mice treated with a 10-day chronic-plus binge ethanol model exhibited enhanced STAT3 activation despite reduced hepatic IL-6R expression, leading to increased expression of neutrophilic activators with colocalization of Ly6G+ leukocytes and STAT3-positive hepatocytes. IL-6 trans signaling preserves hepatocyte STAT3-dependent gene expression and neutrophilic inflammation in AH.

白细胞介素-6反式信号调控酒精相关性肝炎中性粒细胞炎症
酒精相关性肝炎(AH)是一种以肝内嗜中性粒细胞炎症为特征的急慢性肝衰竭。在肝细胞中,IL-6可以通过膜结合(经典信号)或可溶性(反式信号)IL-6受体发出信号,调节肝损伤反应。本研究的目的是确定IL-6反式信号在AH病理生理中的作用。酒精相关性肝病患者肝脏RNA-Seq显示,随着AH严重程度的增加,IL-6受体(IL-6R)表达下降,TGF-β1是IL-6R表达最强的负调节因子;然而,stat3依赖性基因表达在严重AH中增加。在体外,将HepG2细胞暴露于TGF-β1以抑制IL-6R的表达,然后用1)IL-6激活STAT3以刺激经典信号传导或2)重组IL-6/IL-6Rα肽超IL-6激活反式信号传导。当IL-6R受到抑制时,只有hyper-IL-6而不是IL-6能够恢复STAT3的激活。在高il -6刺激的细胞上进行RNA-Seq,得到一个基因标记,鉴定出一组AH患者:1)IL-6TS活性增强;2)肝内嗜中性粒细胞浸润增加;3)白细胞迁移途径转录富集。经10天慢性+狂欢乙醇模型处理的雌性小鼠显示,尽管肝脏IL-6R表达降低,但STAT3激活增强,导致中性粒细胞激活因子表达增加,Ly6G+白细胞和STAT3阳性肝细胞共定位。IL-6反式信号传导维持AH中肝细胞stat3依赖性基因表达和嗜中性粒细胞炎症。
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来源期刊
CiteScore
11.40
自引率
0.00%
发文量
178
审稿时长
30 days
期刊介绍: The American Journal of Pathology, official journal of the American Society for Investigative Pathology, published by Elsevier, Inc., seeks high-quality original research reports, reviews, and commentaries related to the molecular and cellular basis of disease. The editors will consider basic, translational, and clinical investigations that directly address mechanisms of pathogenesis or provide a foundation for future mechanistic inquiries. Examples of such foundational investigations include data mining, identification of biomarkers, molecular pathology, and discovery research. Foundational studies that incorporate deep learning and artificial intelligence are also welcome. High priority is given to studies of human disease and relevant experimental models using molecular, cellular, and organismal approaches.
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