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

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, Craig J. McClain, Arun Sanya, Mack C. Mitchell, Srinivasan Dasarathy, Vijay H. Shah, Naga Chalasani, Samer Gawrieh, Wanzhu Tu, Bruce Barton · 发表于：Science Translational Medicine · 年份：2024 · DOI：10.1126/scitranslmed.adg1915 · 被引用次数：8 · 研究领域：Alcohol Consumption and Health Effects、Diabetes and associated disorders、Liver Disease Diagnosis and Treatment

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 pri...