Rousseau Déborah, Bonnafous Stéphanie, Soysouvanh Frédéric, Sarrail Dorian, Bourinet Manon, Strazzulla Axelle, Patouraux Stéphanie, Borderie Arnaud, Dolfi Bastien, Gallerand Alexandre, Farrugia Marwin A, Orian-Rousseau Véronique, Xu Yingzheng, Williams Jesse W, Ivanov Stoyan, Tran Albert, Anty Rodolphe, Luci Carmelo, Gual Philippe
Université Côte d'Azur, INSERM, U1065, C3M, Nice, France.
Université Côte d'Azur, CHU, INSERM, C3M, Nice, France.
Hepatology. 2025 Jan 14. doi: 10.1097/HEP.0000000000001232.
Alcohol-associated liver disease (ALD) is one of the leading causes of severe liver disease with limited pharmacological treatments for alcohol-associated steatohepatitis. CD44, a glycoprotein mainly expressed in immune cells, has been implicated in multiple inflammatory diseases but has never been studied in the ALD context. We therefore studied its contribution to alcohol-associated steatohepatitis development in mice and its expression in patients with ALD.
Here, we report that liver CD44 expression is associated with liver injury and inflammation and its deficiency ( Cd44-/- ) partially protected mice on chronic plus binge ethanol feeding. CD44 deletion in myeloid cells ( Cd44myel-KO ) recapitulated the same protective effects associated with reduced inflammatory monocyte infiltration and neutrophil activation in the liver and diminished blood neutrophil-lymphocyte ratio. CD44-deficient neutrophils displayed reduced phorbol 12-myristate 13-acetate-induced inflammatory mediator expression and increased phagocytosis of live bacteria. Cd44myel-KO mice were also protected against hepatic steatosis mediated by chronic plus binge ethanol feeding or chronic ethanol feeding due in part to increased SIRT1-mediated fatty acid beta-oxidation. CD44 neutralization with antibodies strongly decreased liver injury and inflammation (hepatic neutrophil frequency) and blood neutrophil-lymphocyte ratio on chronic plus binge ethanol feeding. In samples from patients with ALD, hepatic CD44 expression increased with ALD severity, correlated with hepatic TNFα and CD11b expression, and CD44-expressing neutrophils were enriched in alcohol-associated hepatitis.
Human and experimental evidence supports CD44 as a marker of hepatic inflammation in ALD. In addition, CD44 modulates neutrophil mobilization and functions, and its targeting partially prevents liver inflammation and injury in the context of acute-on-chronic alcohol drinking.
酒精性肝病（ALD）是严重肝病的主要病因之一，针对酒精性脂肪性肝炎的药物治疗有限。CD44是一种主要在免疫细胞中表达的糖蛋白，已被证明与多种炎症性疾病有关，但从未在ALD背景下进行过研究。因此，我们研究了其在小鼠酒精性脂肪性肝炎发展中的作用及其在ALD患者中的表达。
在此，我们报告肝脏CD44表达与肝损伤和炎症相关，其缺失（Cd44-/-）可部分保护慢性加暴饮乙醇喂养的小鼠。髓系细胞中CD44缺失（Cd44myel-KO）重现了相同的保护作用，与肝脏中炎症单核细胞浸润减少、中性粒细胞活化降低以及血液中性粒细胞与淋巴细胞比例降低有关。CD44缺陷的中性粒细胞显示佛波酯12-肉豆蔻酸酯13-乙酸酯诱导的炎症介质表达减少，活细菌吞噬作用增加。Cd44myel-KO小鼠也受到保护，免受慢性加暴饮乙醇喂养或慢性乙醇喂养介导的肝脂肪变性，部分原因是SIRT1介导的脂肪酸β-氧化增加。用抗体中和CD44可强烈降低慢性加暴饮乙醇喂养时的肝损伤和炎症（肝脏中性粒细胞频率）以及血液中性粒细胞与淋巴细胞比例。在ALD患者的样本中，肝脏CD44表达随ALD严重程度增加，与肝脏TNFα和CD11b表达相关，并且表达CD44的中性粒细胞在酒精性肝炎中富集。
人和实验证据支持CD44作为ALD中肝脏炎症的标志物。此外，CD44调节中性粒细胞的动员和功能，在慢性饮酒基础上急性饮酒的情况下，靶向CD44可部分预防肝脏炎症和损伤。
