Therapeutic inhibition of inflammatory monocyte recruitment reduces steatohepatitis and liver fibrosis
Therapeutic inhibition of inflammatory monocyte recruitment reduces steatohepatitis and liver fibrosis
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DOI：
10.1002/hep.29544
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发表时间：
2018-04-01
期刊：
影响因子：
13.5
通讯作者：
Tacke, Frank
中科院分区：
文献类型：
--
作者：
Krenkel, Oliver;Puengel, Tobias;Tacke, Frank
巨噬细胞是非酒精性脂肪性肝炎（NASH）肝纤维化进展和消退的关键调节因子。肝巨噬细胞包括常驻吞噬细胞、枯否细胞和单核细胞衍生的细胞，其通过趋化因子受体C-C基序趋化因子受体2（CCR 2）募集。我们旨在阐明通过使用赛尼克韦罗（CVC）（一种口服双重趋化因子受体CCR2/CCR5拮抗剂，其正在临床评估中）抑制NASH模型中单核细胞浸润的治疗效果。分析来自NASH患者的人肝组织的CCR2（+）巨噬细胞，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CVC的施用。在来自17名患者和4名对照的人类肝脏中，CCR2（+）巨噬细胞的增加与NASH严重程度和纤维化阶段平行，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。与人类疾病相似，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，用CVC治疗性处理显著减少肝Ly-6C（+）MoMF的募集。在实验性脂肪性肝炎伴肥胖症中，治疗性CVC应用显著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。重要的是，CVC在损伤停止后不延迟纤维化消退。RNA测序分析显示，MoMF，而不是Kupffer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Kupffer细胞激活与炎症启动和脂质代谢相关的途径。结论：CCR2（+）单核细胞募集的药理学抑制有效地改善胰岛素抵抗、肝脏炎症和纤维化，证实了CVC在NASH患者中的治疗潜力。（肝病学2018; 67：1270 - 1283）
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)