Li Jichen, Wang Ben, Wang Shunjie, Wang Jieguo, Zhou Anqi, Gong Shanwen, Wang Yu, Miao Xiulian, Guo Yan, Wang Hao, Ge Hailong
State Key Laboratory of Natural Medicines, Department of Pharmacology, China Pharmaceutical University, Nanjing, China.
Pediatric Intensive Care Unit, Children's Hospital of Nanjing Medical University, Nanjing, China.
Life Sci. 2025 Feb 15;363:123409. doi: 10.1016/j.lfs.2025.123409. Epub 2025 Jan 20.
Alcoholic liver disease (ALD) is characterized by aberrant lipid metabolism and chronic inflammation that eventually give rise to cirrhosis and hepatocellular carcinoma. In the present study we investigated the contribution of CC motif chemokine ligand 11 (CCL11) to ALD pathogenesis.
ALD was induced in mice by binge ethanol gavage or chronic ethanol feeding.
Bioinformatic analysis of sequencing data indicated that CCL11 expression was up-regulated in hepatocytes from mice subjected to ethanol feeding compared to those from the control mice. Exposure to ethanol led to CCL11 up-regulation in primary murine hepatocytes in vitro. Consistently, Oil Red O (ORO) staining detected elevated lipid accumulation whereas quantitative PCR (qPCR) detected augmented expression of pro-inflammatory mediators in primary murine hepatocytes treated with recombinant CCL11. On the contrary, CCL11 knockout mice (KO) developed a less severe form of ALD compared to wild type littermates when subjected to either binge or chronic ethanol feeding. Finally, CCL11 antagonism by administration with an inhibitor to CCL11 receptor CCR3 (CCR3i) attenuated ALD in mice.
Our data support a role for CCL11 in ALD pathogenesis and provide proof-of-concept that targeting CCL11 can be considered as a therapeutic approach for ALD intervention.
酒精性肝病（ALD）的特征是脂质代谢异常和慢性炎症，最终导致肝硬化和肝细胞癌。在本研究中，我们调查了CC基序趋化因子配体11（CCL11）在ALD发病机制中的作用。
通过暴饮乙醇灌胃或慢性乙醇喂养在小鼠中诱导ALD。
对测序数据的生物信息学分析表明，与对照小鼠相比，乙醇喂养小鼠的肝细胞中CCL11表达上调。体外乙醇暴露导致原代小鼠肝细胞中CCL11上调。同样，油红O（ORO）染色检测到脂质积累增加，而定量PCR（qPCR）检测到用重组CCL11处理的原代小鼠肝细胞中促炎介质的表达增加。相反，与野生型同窝小鼠相比，CCL11基因敲除小鼠（KO）在暴饮或慢性乙醇喂养时发生的ALD形式较轻。最后，通过给予CCL11受体CCR3抑制剂（CCR3i）拮抗CCL11可减轻小鼠的ALD。
我们的数据支持CCL11在ALD发病机制中的作用，并提供了概念验证，即靶向CCL11可被视为ALD干预的治疗方法。
