CD44 in myEloid cells is a major driver of liver inflammation and injury in alcohol-related liver disease

IF 12.9 1区 医学 Q1 GASTROENTEROLOGY & HEPATOLOGY
Déborah Rousseau, Stéphanie Bonnafous, Frédéric Soysouvanh, Dorian Sarrail, Manon Bourinet, Axelle Strazzulla, Stéphanie Patouraux, Arnaud Borderie, Bastien Dolfi, Alexandre Gallerand, Marwin A Farrugia, Véronique Orian-rousseau, Yingzheng Xu, Jesse W. Williams, Stoyan Ivanov, Albert Tran, Rodolphe Anty, Carmelo Luci, Philippe Gual
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Abstract

Background and Aims: Alcohol-related liver disease (ALD) is one of the leading causes of severe liver disease with limited pharmacological treatments for alcohol-related steatohepatitis (ASH). 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 ASH development in mice and its expression in ALD patients Approach and Results: Here, we report that liver CD44 expression is associated with liver injury and inflammation and its deficiency (Cd44 -/-) partially protected mice upon chronic plus binge ethanol feeding (CPB-EtOH). CD44 deletion in myeloid cells (Cd44 myel-KO ) recapitulated the same protective effects associated with reduced inflammatory monocyte infiltration and neutrophil activation in the liver and diminished blood neutrophil-lymphocyte ratio (NLR). CD44-deficient neutrophils displayed reduced PMA-induced inflammatory mediator expression and increased phagocytosis of live bacteria. Cd44 myel-KO mice were also protected against hepatic steatosis mediated by CPB-EtOH 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 NLR upon CPB-EtOH. In samples from ALD patients, hepatic CD44 expression increased with ALD severity, correlated with hepatic TNFα and CD11b expression, and CD44-expressing neutrophils were enriched in alcohol-associated hepatitis. Conclusions: 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.
髓系细胞中的CD44是酒精相关性肝病中肝脏炎症和损伤的主要驱动因素
背景和目的:酒精相关性肝脏疾病(ALD)是严重肝脏疾病的主要原因之一,酒精相关性脂肪性肝炎(ASH)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,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,我们研究了它对小鼠ASH发展及其在ALD患者中的表达的贡献方法和结果:在这里,我们报告了肝脏CD44表达与肝损伤和炎症有关,并且其缺乏(CD44 -/-)部分保护慢性加暴乙醇喂养(CPB-EtOH)小鼠。髓细胞中CD44缺失(CD44 myl - ko)再现了与肝脏中炎症单核细胞浸润和中性粒细胞活化减少以及血液中性粒细胞-淋巴细胞比率(NLR)降低相关的相同保护作用。缺乏cd44的中性粒细胞表现出pma诱导的炎症介质表达减少和活细菌的吞噬增加。Cd44 myel-KO小鼠也被保护免受CPB-EtOH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。抗体中和CD44可显著降低CPB-EtOH后的肝损伤和炎症(肝中性粒细胞频率)和血液NLR。在ALD患者的样本中,肝脏CD44表达随着ALD严重程度的增加而增加,与肝脏TNFα和CD11b表达相关,表达CD44的中性粒细胞在酒精相关性肝炎中富集。结论:人类和实验证据支持CD44作为ALD患者肝脏炎症的标志物。此外,CD44调节中性粒细胞的动员和功能,其靶向部分预防急性慢性饮酒背景下的肝脏炎症和损伤。
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来源期刊
Hepatology
Hepatology 医学-胃肠肝病学
CiteScore
27.50
自引率
3.70%
发文量
609
审稿时长
1 months
期刊介绍: HEPATOLOGY is recognized as the leading publication in the field of liver disease. It features original, peer-reviewed articles covering various aspects of liver structure, function, and disease. The journal's distinguished Editorial Board carefully selects the best articles each month, focusing on topics including immunology, chronic hepatitis, viral hepatitis, cirrhosis, genetic and metabolic liver diseases, liver cancer, and drug metabolism.
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