In vivo Bruton’s tyrosine kinase inhibition attenuates alcohol-associated liver disease by regulating CD84-mediated granulopoiesis
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Published:2024-08-07
Issue:759
Volume:16
Page:
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ISSN:1946-6234
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Container-title:Science Translational Medicine
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language:en
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Short-container-title:Sci. Transl. Med.
Author:
Nagesh Prashanth Thevkar1, Cho Yeonhee1ORCID, Zhuang Yuan1ORCID, Babuta Mrigya1ORCID, Ortega-Ribera Marti1ORCID, Joshi Radhika1, Brezani Veronika1ORCID, Patel Arman1, Datta Aditi Ashish1, Brezani Viliam1, Hsieh Yun-Cheng1, Ramos Adriana1, Mehta Jeeval1, Copeland Christopher1ORCID, Kanata Eleni2ORCID, Jiang Zhenghui Gordon1ORCID, Vlachos Ioannis2ORCID, Asara John3ORCID, , Szabo Gyongyi1ORCID, Bataller Ramon, McClain Craig J., Sanya Arun, Mitchell Mack C., Dasarathy Srinivasan, Shah Vijay H., Chalasani Naga, Gawrieh Samer, Tu Wanzhu, Barton Bruce
Affiliation:
1. Department of Medicine, Division of Gastroenterology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA. 2. Department of Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA. 3. Division of Signal Transduction, Beth Israel Deaconess Medical Center and Department of Medicine, Harvard Medical School, Boston, MA 02215, USA.
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.
Publisher
American Association for the Advancement of Science (AAAS)
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