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

IF 15.8 1区 医学 Q1 CELL BIOLOGY Science Translational Medicine Pub Date : 2024-08-07 DOI:10.1126/scitranslmed.adg1915
Prashanth Thevkar Nagesh, Yeonhee Cho, Yuan Zhuang, Mrigya Babuta, Marti Ortega-Ribera, Radhika Joshi, Veronika Brezani, Arman Patel, Aditi Ashish Datta, Viliam Brezani, Yun-Cheng Hsieh, Adriana Ramos, Jeeval Mehta, Christopher Copeland, Eleni Kanata, Zhenghui Gordon Jiang, Ioannis Vlachos, John Asara, AlcHepNet Consortium, Gyongyi Szabo
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Abstract

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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体内布鲁顿酪氨酸激酶抑制剂通过调节 CD84 介导的粒细胞生成,减轻酒精相关性肝病。
严重酒精相关性肝炎(AH)是一种危及生命的酒精相关性肝病。肝脏中性粒细胞浸润是酒精中毒性肝炎的标志,但酒精对中性粒细胞功能的影响仍然难以捉摸。找到减少中性粒细胞介导的肝损伤的治疗靶点至关重要。布鲁顿酪氨酸激酶(BTK)在中性粒细胞的发育和功能中发挥着重要作用;然而,BTK在AH中的作用尚不清楚。通过对循环中性粒细胞进行 RNA 测序,我们发现与健康对照组相比,AH 患者的 Btk 表达量(P = 0.05)和磷酸化 BTK(pBTK)均有所增加。在体外,生理相关剂量的酒精会迅速诱导中性粒细胞中由 TLR4 介导的 pBTK。在AH的临床前模型中,服用小分子BTK抑制剂(evobrutinib)或髓细胞特异性Btk基因敲除可减少促炎细胞因子,减轻中性粒细胞介导的肝损伤。我们发现,pBTK 对酒精诱导的骨髓粒细胞生成和肝脏中性粒细胞浸润至关重要。在体内,抑制 BTK 或骨髓特异性 Btk 基因敲除可减少小鼠 AH 模型中的粒细胞生成、循环中性粒细胞、肝脏中性粒细胞浸润和肝损伤。从机理上讲,我们利用液相色谱-串联质谱法确定了 CD84 是 BTK 的激酶靶点,而 BTK 参与粒细胞生成。在体外,CD84能促进酒精诱导的白细胞介素-1β和肿瘤坏死因子-α在原代人中性粒细胞中的表达,而CD84阻断抗体能抑制酒精诱导的白细胞介素-1β和肿瘤坏死因子-α的表达。我们的研究结果确定了 BTK 和 CD84 在调节中性粒细胞炎症和粒细胞生成中的作用,对 AH 具有潜在的治疗意义。
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来源期刊
Science Translational Medicine
Science Translational Medicine CELL BIOLOGY-MEDICINE, RESEARCH & EXPERIMENTAL
CiteScore
26.70
自引率
1.20%
发文量
309
审稿时长
1.7 months
期刊介绍: Science Translational Medicine is an online journal that focuses on publishing research at the intersection of science, engineering, and medicine. The goal of the journal is to promote human health by providing a platform for researchers from various disciplines to communicate their latest advancements in biomedical, translational, and clinical research. The journal aims to address the slow translation of scientific knowledge into effective treatments and health measures. It publishes articles that fill the knowledge gaps between preclinical research and medical applications, with a focus on accelerating the translation of knowledge into new ways of preventing, diagnosing, and treating human diseases. The scope of Science Translational Medicine includes various areas such as cardiovascular disease, immunology/vaccines, metabolism/diabetes/obesity, neuroscience/neurology/psychiatry, cancer, infectious diseases, policy, behavior, bioengineering, chemical genomics/drug discovery, imaging, applied physical sciences, medical nanotechnology, drug delivery, biomarkers, gene therapy/regenerative medicine, toxicology and pharmacokinetics, data mining, cell culture, animal and human studies, medical informatics, and other interdisciplinary approaches to medicine. The target audience of the journal includes researchers and management in academia, government, and the biotechnology and pharmaceutical industries. It is also relevant to physician scientists, regulators, policy makers, investors, business developers, and funding agencies.
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