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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引用次数: 0
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.
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.