Center for Liver Disease Research, Department of Inflammation and Immunity, Cleveland Clinic, Cleveland, Ohio, USA.
Department of Anesthesiology, McGovern Medical School, University of Texas Health Science Center at Houston, Houston, Texas, USA.
JCI Insight. 2021 Jun 8;6(11):141420. doi: 10.1172/jci.insight.141420.
The chemokine system of ligands and receptors is implicated in the progression of alcohol-associated hepatitis (AH). Finding upstream regulators could lead to novel therapies. This study involved coordinated expression of chemokines in livers of healthy controls (HC) and patients with AH in 2 distinct cohorts of patients with various chronic liver diseases. Studies in cultured hepatocytes and in tissue-specific KO were used for mechanistic insight into a potential upstream regulator of chemokine expression in AH. Selected C-X-C chemokine members of the IL-8 chemokine family and C-C chemokine CCL20 were highly associated with AH compared with HC but not in patients with liver diseases of other etiologies (nonalcoholic fatty liver disease [NAFLD] and hepatitis C virus [HCV]). Our previous studies implicate macrophage migration inhibitory factor (MIF) as a pleiotropic cytokine/chemokine with the potential to coordinately regulate chemokine expression in AH. LPS-stimulated expression of multiple chemokines in cultured hepatocytes was dependent on MIF. Gao-binge ethanol feeding to mice induced a similar coordinated chemokine expression in livers of WT mice; this was prevented in hepatocyte-specific Mif-KO (MifΔHep) mice. This study demonstrates that patients with AH exhibit a specific, coordinately expressed chemokine signature and that hepatocyte-derived MIF might drive this inflammatory response.
趋化因子系统的配体和受体与酒精相关性肝炎（AH）的进展有关。寻找上游调节剂可能会导致新的治疗方法。本研究涉及在两个不同的慢性肝病患者队列中，协调表达健康对照（HC）和 AH 患者肝脏中的趋化因子。在培养的肝细胞和组织特异性 KO 中进行的研究为 AH 中趋化因子表达的潜在上游调节剂提供了机制见解。与 HC 相比，IL-8 趋化因子家族的某些 C-X-C 趋化因子成员和 C-C 趋化因子 CCL20 与 AH 高度相关，但与其他病因（非酒精性脂肪性肝病[NAFLD]和丙型肝炎病毒[HCV]）的肝病患者无关。我们之前的研究表明，巨噬细胞移动抑制因子（MIF）作为一种具有潜在协调调节 AH 中趋化因子表达能力的多效细胞因子/趋化因子。LPS 刺激培养的肝细胞中多种趋化因子的表达依赖于 MIF。高 binge 乙醇喂养诱导 WT 小鼠肝脏中趋化因子的相似协调表达；在肝细胞特异性 Mif-KO（MifΔHep）小鼠中则可预防。本研究表明，AH 患者表现出特定的、协调表达的趋化因子特征，而肝细胞衍生的 MIF 可能驱动这种炎症反应。
