Xie Huiyuan, Zhang Pingping, Yang Shanru, Du Jia, Ren Yan, Gao Xianxian, Li Na, Yang Tao, Ma Yang, Hou Xin
Department of Laboratory Medicine, The First Affiliated Hospital of Ningbo University, Ningbo, 315010, Zhejiang, China.
Institute of Clinical Pharmacology, Key Laboratory of Anti-Inflammatory and Immune Medicine, Ministry of Education, Anhui Collaborative Innovation Center of Anti-Inflammatory and Immune Medicine, Anhui Medical University, Hefei, 230032, Anhui, China.
J Gastroenterol. 2025 Mar 20. doi: 10.1007/s00535-025-02240-0.
Myeloid cells play a pivotal role in the pathogenesis of alcoholic liver disease (ALD), yet the mechanisms regulating their function and specific contributions to ALD remain inadequately understood. This study aims to investigate the role of mesencephalic astrocyte-derived neurotrophic factor (MANF) in the development of ALD.
Myeloid-specific Manf knockout mice and wild-type controls were fed an ethanol-based diet for 10 days, followed by a single ethanol binge. Hepatic MANF levels, along with the correlation between MANF and inflammatory factors in patients with alcoholic hepatitis, were analyzed using the GSE28619 dataset.
Our study demonstrated that myeloid MANF expression in the liver was upregulated following chronic-plus-binge ethanol exposure. Deletion of the Manf gene in myeloid cells, including neutrophils, exacerbated ethanol-induced liver injury, steatosis, neutrophil infiltration, and reactive oxygen species production. Mechanistic analysis revealed that MANF promotes neutrophil miR-223 expression, a key anti-inflammatory factor in these cells. MANF enhances miR-223 transcription by increasing the expression of the transcription factor PU.1 via p38 mitogen-activated protein kinase signaling. In addition, hepatic MANF levels were elevated in patients with alcoholic hepatitis and correlated with IL-6, IL-1β, and phagocytic oxidase (phox) p47levels.
Myeloid-derived MANF mitigates alcohol-induced liver injury by upregulating the neutrophilic p38-PU.1-miR-223 axis.
髓样细胞在酒精性肝病（ALD）的发病机制中起关键作用，但其功能调节机制以及对ALD的具体作用仍未得到充分了解。本研究旨在探讨中脑星形胶质细胞源性神经营养因子（MANF）在ALD发生发展中的作用。
将髓样特异性Manf基因敲除小鼠和野生型对照小鼠给予含乙醇饮食10天，随后进行单次乙醇暴饮。使用GSE28619数据集分析肝脏中MANF水平以及酒精性肝炎患者中MANF与炎症因子之间的相关性。
我们的研究表明，慢性加暴饮乙醇暴露后肝脏中髓样MANF表达上调。在包括中性粒细胞在内的髓样细胞中删除Manf基因会加剧乙醇诱导的肝损伤、脂肪变性、中性粒细胞浸润和活性氧生成。机制分析显示，MANF促进中性粒细胞miR-223表达，miR-223是这些细胞中的关键抗炎因子。MANF通过p38丝裂原活化蛋白激酶信号通路增加转录因子PU.1的表达来增强miR-223转录。此外，酒精性肝炎患者肝脏中MANF水平升高，且与IL-6、IL-1β和吞噬氧化酶（phox）p47水平相关。
髓样来源的MANF通过上调中性粒细胞的p38-PU.1-miR-223轴减轻酒精诱导的肝损伤。
