Dopamine receptor D2 antagonism normalizes profibrotic macrophage-endothelial crosstalk in non-alcoholic steatohepatitis
Dopamine receptor D2 antagonism normalizes profibrotic macrophage-endothelial crosstalk in non-alcoholic steatohepatitis
复制标题
多巴胺受体 D2 拮抗作用使非酒精性脂肪性肝炎中促纤维化巨噬细胞-内皮细胞串扰正常化。
DOI：
10.1016/j.jhep.2021.09.032
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发表时间：
2022-01-14
影响因子：
25.7
通讯作者：
Cao, Zhongwei
中科院分区：
文献类型：
--
作者：
Qing, Jie;Ren, Yafeng;Cao, Zhongwei
背景与目的：肝纤维化是非酒精性脂肪性肝炎（NASH）的主要组织学决定因素之一，目前尚无有效的治疗方法。虽然 Hippo/YAP（Yes 相关蛋白）信号传导对于肝脏再生至关重要，但其异常激活常常导致纤维化和肿瘤发生。阐明 YAP 在肝脏修复中的“特定情况”贡献可能有助于选择性地绕过纤维化并保留肝脏疾病中的促再生 YAP 功能。方法：我们使用小鼠肝纤维化和小型猪 NASH 模型，以及肝硬化患者的肝活检。进行了单细胞 RNA 测序 (scRNA-Seq)，并使用 G 蛋白偶联受体 (GPCR) 配体筛选系统来鉴定细胞选择性 YAP 抑制剂。结果：患有肝纤维化的人类和小鼠肝脏中巨噬细胞中的 YAP 水平升高。在骨髓细胞中特别缺乏 Yap1 的小鼠中观察到 I 型干扰素的增加和肝纤维化的减弱，为巨噬细胞 YAP 的纤维形成作用提供了进一步的证据。 ScRNA-Seq 进一步表明，巨噬细胞中存在缺陷的 YAP 通路信号传导减少了纤维化血管内皮细胞亚群，该亚群表现出促纤维化分子特征，例如血管分泌 CTGF 和 VCAM1 表达。为了特异性靶向巨噬细胞中的纤维化 YAP，我们利用 GPCR 配体筛选系统并鉴定了一种多巴胺受体 D2 (DRD2) 拮抗剂，该拮抗剂可选择性阻断巨噬细胞而非肝细胞中的 YAP。巨噬细胞 DRD2 的遗传和药理学靶向可减轻肝纤维化。在重现人类病理学的大型动物（小型猪）NASH 模型中，DRD2 拮抗剂可阻断纤维化并恢复肝脏结构。结论：DRD2 拮抗剂选择性地靶向巨噬细胞和 CTGF(+)VCAM1(+) 血管生态位之间 YAP 依赖性纤维化串扰，在啮齿动物和大型动物模型中促进肝脏再生而不是纤维化。简单总结：肝脏纤维化是肝脏纤维化的主要组织学决定因素之一。非酒精性脂肪性肝炎（NASH），一种与全球范围内代谢综合征激增同时发生的疾病。我们的研究表明，巨噬细胞特异性的 Yes 相关蛋白 (YAP) 缺陷可减轻肝纤维化。在啮齿动物和大型动物模型中，多巴胺受体 D2 (DRD2) 拮抗剂选择性阻断巨噬细胞中的 YAP 并阻止肝纤维化，因此具有治疗 NASH 的潜力。 (C) 2021 年欧洲肝脏研究协会。由 Elsevier B.V. 出版。保留所有权利。
Background & Aims: Currently there is no effective treatment for liver fibrosis, which is one of the main histological determinants of non-alcoholic steatohepatitis (NASH). While Hippo/YAP (Yes-associated protein) signaling is essential for liver regeneration, its aberrant activation frequently leads to fibrosis and tumorigenesis. Unravelling "context-specific" contributions of YAP in liver repair might help selectively bypass fibrosis and preserve the pro-regenerative YAP function in hepatic diseases.Methods: We used murine liver fibrosis and minipig NASH models, and liver biopsies from patients with cirrhosis. Single-cell RNA-sequencing (scRNA-Seq) was performed, and a G-protein-coupled receptor (GPCR) ligand screening system was used to identify cell-selective YAP inhibitors.Results: YAP levels in macrophages are increased in the livers of humans and mice with liver fibrosis. The increase in type I interferon and attenuation of hepatic fibrosis observed in mice specifically lacking Yap1 in myeloid cells provided further evidence for the fibrogenic role of macrophage YAP. ScRNA-Seq further showed that defective YAP pathway signaling in macrophages diminished a fibrogenic vascular endothelial cell subset that exhibited profibrotic molecular signatures such as angiocrine CTGF and VCAM1 expression. To specifically target fibrogenic YAP in macrophages, we utilized a GPCR ligand screening system and identified a dopamine receptor D2 (DRD2) antagonist that selectively blocked YAP in macrophages but not hepatocytes. Genetic and pharmacological targeting of macrophage DRD2 attenuated liver fibrosis. In a large animal (minipig) NASH model recapitulating human pathology, the DRD2 antagonist blocked fibrosis and restored hepatic architecture.Conclusions: DRD2 antagonism selectively targets YAP-dependent fibrogenic crosstalk between macrophages and CTGF(+)VCAM1(+) vascular niche, promoting liver regeneration over fibrosis in both rodent and large animal models.Lay summary: Fibrosis in the liver is one of the main histological determinants of non-alcoholic steatohepatitis (NASH), a disease paralleling a worldwide surge in metabolic syndromes. Our study demonstrates that a macrophage-specific deficiency in Yesassociated protein (YAP) attenuates liver fibrosis. Dopamine receptor D2 (DRD2) antagonism selectively blocks YAP in macrophages and thwarts liver fibrosis in both rodent and large animal models, and thus holds potential for the treatment of NASH. (C) 2021 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.