The Bile Acid Receptor GPBAR1 Modulates CCL2/CCR2 Signaling at the Liver Sinusoidal/Macrophage Interface and Reverses Acetaminophen-Induced Liver Toxicity
The Bile Acid Receptor GPBAR1 Modulates CCL2/CCR2 Signaling at the Liver Sinusoidal/Macrophage Interface and Reverses Acetaminophen-Induced Liver Toxicity
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DOI：
10.4049/jimmunol.1901427
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发表时间：
2020-05-01
影响因子：
4.4
通讯作者：
Fiorucci, Stefano
中科院分区：
文献类型：
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作者：
Biagioli, Michele;Carino, Adriana;Fiorucci, Stefano
对乙酰氨基酚（乙酰对氨基苯酚[APAP]）引起的药物性肝损伤是一些西方国家急性肝衰竭和肝移植的主要原因。虽然 APAP 代谢物产生的直接毒性是早期肝细胞损伤的关键决定因素，但先天免疫细胞的募集在疾病进展中发挥着机械作用，决定了临床结果。 GPBAR1 是一种次级胆汁酸的 G 蛋白偶联受体，位于肝窦细胞和先天免疫之间的界面。在本报告中，我们利用遗传和药理学方法证明，虽然 Gpbar1 基因缺失会加重肝损伤的严重程度，但 6 beta-乙基-3a,7b-二羟基-5b-cholan-24-ol 对其进行药理学激活可挽救小鼠免受 APAP 引起的肝损伤。这种保护作用得到了肝脏对单核细胞来源的巨噬细胞的募集的强烈减弱及其向抗炎表型的复极化的支持。通过氯化钆预处理消除巨噬细胞消除了疾病的发展，而通过脾源性巨噬细胞移植重建巨噬细胞则以 GPBAR1 依赖性方式恢复了对 APAP 的敏感性。 RNA 测序分析表明，GPBAR1 激动作用调节多种途径的表达，包括趋化因子 CCL2 及其受体 CCR2。用抗 CCL2 mAb 治疗野生型小鼠可减轻肝损伤的严重程度。我们证明 GPBAR1 激动对 CCL2 产生的负调节是启动子依赖性的，并且涉及 FOXO1。总之，我们证明 GPBAR1 是正弦细胞/巨噬细胞界面 CCL2/CCR2 轴的上游调节剂，为治疗 APAP 引起的肝损伤提供了新的靶点。
Drug-induced liver injury caused by acetaminophen (acetyl-para-aminophenol [APAP]) is the main cause of acute liver failure and liver transplantation in several Western countries. Whereas direct toxicity exerted by APAP metabolites is a key determinant for early hepatocytes injury, the recruitment of cells of innate immunity exerts a mechanistic role in disease progression, determining the clinical outcomes. GPBAR1 is a G protein-coupled receptor for secondary bile acids placed at the interface between liver sinusoidal cells and innate immunity. In this report, using genetic and pharmacological approaches, we demonstrate that whereas Gpbar1 gene deletion worsens the severity of liver injury, its pharmacological activation by 6 beta-ethyl-3a,7b-dihydroxy-5b-cholan-24-ol rescues mice from liver injury caused by APAP. This protective effect was supported by a robust attenuation of liver recruitment of monocyte-derived macrophages and their repolarization toward an anti-inflammatory phenotype. Macrophage depletion by gadolinium chloride pretreatment abrogated disease development, whereas their reconstitution by spleen-derived macrophage transplantation restored the sensitivity to APAP in a GPBAR1-dependent manner. RNA sequencing analyses demonstrated that GPBAR1 agonism modulated the expression of multiple pathways, including the chemokine CCL2 and its receptor, CCR2. Treating wild-type mice with an anti-CCL2 mAb attenuated the severity of liver injury. We demonstrated that negative regulation of CCL2 production by GPBAR1 agonism was promoter dependent and involved FOXO1. In conclusion, we have shown that GPBAR1 is an upstream modulator of CCL2/CCR2 axis at the sinusoidal cell/macrophage interface, providing a novel target in the treatment of liver damage caused by APAP.