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In vivo Bruton’s tyrosine kinase inhibition attenuates alcohol-associated liver disease by regulating CD84-mediated granulopoiesis

粒细胞生成 药理学 酪氨酸激酶 布鲁顿酪氨酸激酶 癌症研究 医学 促炎细胞因子 化学 生物 免疫学 炎症 细胞生物学 信号转导 造血 生物化学 干细胞
作者
Prashanth Thevkar Nagesh,Yeonhee Cho,Yuan Zhuang,Mrigya Babuta,Martí Ortega‐Ribera,Radhika Joshi,Veronika Brezáni,Arman Patel,Aditi Ashish Datta,Veronika Brezáni,Yun‐Cheng Hsieh,Adriana Ramos,Jeeval Mehta,Christopher Copeland,Eleni Kanata,Z. Gordon Jiang,Ioannis S. Vlachos,John M. Asara,Gyöngyi Szabó,Ramón Bataller
出处
期刊:Science Translational Medicine [American Association for the Advancement of Science (AAAS)]
卷期号:16 (759)
标识
DOI:10.1126/scitranslmed.adg1915
摘要

Severe alcohol-associated hepatitis (AH) is a life-threatening form of alcohol-associated liver disease. Liver neutrophil infiltration is a hallmark of AH, yet the effects of alcohol on neutrophil functions remain elusive. Identifying therapeutic targets to reduce neutrophil-mediated liver damage is essential. Bruton’s tyrosine kinase (BTK) plays an important role in neutrophil development and function; however, the role of BTK in AH is unknown. Using RNA sequencing of circulating neutrophils, we found an increase in Btk expression ( P = 0.05) and phosphorylated BTK (pBTK) in patients with AH compared with healthy controls. In vitro, physiologically relevant doses of alcohol resulted in a rapid, TLR4-mediated induction of pBTK in neutrophils. In a preclinical model of AH, administration of a small-molecule BTK inhibitor (evobrutinib) or myeloid-specific Btk knockout decreased proinflammatory cytokines and attenuated neutrophil-mediated liver damage. We found that pBTK was essential for alcohol-induced bone marrow granulopoiesis and liver neutrophil infiltration. In vivo, BTK inhibition or myeloid-specific Btk knockout reduced granulopoiesis, circulating neutrophils, liver neutrophil infiltration, and liver damage in a mouse model of AH. Mechanistically, using liquid chromatography–tandem mass spectrometry, we identified CD84 as a kinase target of BTK, which is involved in granulopoiesis. In vitro, CD84 promoted alcohol-induced interleukin-1β and tumor necrosis factor–α in primary human neutrophils, which was inhibited by CD84-blocking antibody treatment. Our findings define the role of BTK and CD84 in regulating neutrophil inflammation and granulopoiesis, with potential therapeutic implications in AH.
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