Macrophages are key regulators of liver fibrosis progression and regression in nonalcoholic steatohepatitis (NASH). Liver macrophages comprise resident phagocytes, Kupffer cells, and monocyte‐derived cells, which are recruited through the chemokine receptor C‐C motif chemokine receptor 2 (CCR2). We aimed at elucidating the therapeutic effects of inhibiting monocyte infiltration in NASH models by using cenicriviroc (CVC), an oral dual chemokine receptor CCR2/CCR5 antagonist that is under clinical evaluation. Human liver tissues from NASH patients were analyzed for CCR2+ macrophages, and administration of CVC was tested in mouse models of steatohepatitis, liver fibrosis progression, and fibrosis regression. In human livers from 17 patients and 4 controls, CCR2+ macrophages increased parallel to NASH severity and fibrosis stage, with a concomitant inflammatory polarization of these cluster of differentiation 68+, portal monocyte‐derived macrophages (MoMF). Similar to human disease, we observed a massive increase of hepatic MoMF in experimental models of steatohepatitis and liver fibrosis. Therapeutic treatment with CVC significantly reduced the recruitment of hepatic Ly‐6C+ MoMF in all models. In experimental steatohepatitis with obesity, therapeutic CVC application significantly improved insulin resistance and hepatic triglyceride levels. In fibrotic steatohepatitis, CVC treatment ameliorated histological NASH activity and hepatic fibrosis. CVC inhibited the infiltration of Ly‐6C+ monocytes, without direct effects on macrophage polarization, hepatocyte fatty acid metabolism, or stellate cell activation. Importantly, CVC did not delay fibrosis resolution after injury cessation. RNA sequencing analysis revealed that MoMF, but not Kupffer cells, specifically up‐regulate multiple growth factors and cytokines associated with fibrosis progression, while Kupffer cells activated pathways related to inflammation initiation and lipid metabolism. Conclusion: Pharmacological inhibition of CCR2+ monocyte recruitment efficiently ameliorates insulin resistance, hepatic inflammation, and fibrosis, corroborating the therapeutic potential of CVC in patients with NASH. (Hepatology 2018;67:1270‐1283)

中文翻译：

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炎症性单核细胞募集的治疗抑制可减少脂肪性肝炎和肝纤维化

巨噬细胞是非酒精性脂肪性肝炎 (NASH) 中肝纤维化进展和消退的关键调节剂。肝巨噬细胞包括常驻吞噬细胞、库普弗细胞和单核细胞衍生细胞，它们通过趋化因子受体 C-C 基序趋化因子受体 2 (CCR2) 募集。我们旨在阐明通过使用西尼昔韦罗 (CVC) 抑制 NASH 模型中单核细胞浸润的治疗效果，这是一种正在临床评估的口服双趋化因子受体 CCR2/CCR5 拮抗剂。对来自 NASH 患者的人肝组织进行了 CCR2+ 巨噬细胞分析，并在脂肪性肝炎、肝纤维化进展和纤维化消退的小鼠模型中测试了 CVC 的给药。在来自 17 名患者和 4 名对照组的人类肝脏中，CCR2+ 巨噬细胞随着 NASH 的严重程度和纤维化阶段而增加，伴随着这些分化簇 68+、门静脉单核细胞衍生的巨噬细胞 (MoMF) 的炎症极化。与人类疾病类似，我们在脂肪性肝炎和肝纤维化的实验模型中观察到肝脏 MoMF 的大量增加。在所有模型中，CVC 治疗显着减少了肝脏 Ly-6C+ MoMF 的募集。在伴有肥胖的实验性脂肪性肝炎中，治疗性 CVC 应用显着改善了胰岛素抵抗和肝脏甘油三酯水平。在纤维化脂肪性肝炎中，CVC 治疗改善了组织学 NASH 活性和肝纤维化。CVC 抑制 Ly-6C+ 单核细胞的浸润，对巨噬细胞极化、肝细胞脂肪酸代谢或星状细胞活化没有直接影响。重要的，CVC 不会延迟损伤停止后纤维化的消退。RNA测序分析显示，MoMF而非库普弗细胞特异性上调与纤维化进展相关的多种生长因子和细胞因子，而库普弗细胞激活与炎症起始和脂质代谢相关的通路。结论：药理学抑制 CCR2+ 单核细胞募集可有效改善胰岛素抵抗、肝脏炎症和纤维化，证实 CVC 对 NASH 患者的治疗潜力。（肝病学 2018 年；67：1270-1283）CCR2+ 单核细胞募集的药理学抑制可有效改善胰岛素抵抗、肝脏炎症和纤维化，证实 CVC 在 NASH 患者中的治疗潜力。（肝病学 2018 年；67：1270-1283）CCR2+ 单核细胞募集的药理学抑制可有效改善胰岛素抵抗、肝脏炎症和纤维化，证实 CVC 在 NASH 患者中的治疗潜力。（肝病学 2018 年；67：1270-1283）