{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,17]],"date-time":"2026-07-17T00:13:24Z","timestamp":1784247204761,"version":"3.55.0"},"reference-count":62,"publisher":"American Association for the Advancement of Science (AAAS)","issue":"759","content-domain":{"domain":["www.science.org"],"crossmark-restriction":true},"short-container-title":["Sci. Transl. Med."],"published-print":{"date-parts":[[2024,8,7]]},"abstract":"<jats:p>\n            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\u2019s 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\n            <jats:italic>\n              <jats:italic>Btk<\/jats:italic>\n            <\/jats:italic>\n            expression (\n            <jats:italic>P<\/jats:italic>\n            = 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\n            <jats:italic>Btk<\/jats:italic>\n            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\n            <jats:italic>Btk<\/jats:italic>\n            knockout reduced granulopoiesis, circulating neutrophils, liver neutrophil infiltration, and liver damage in a mouse model of AH. Mechanistically, using liquid chromatography\u2013tandem mass spectrometry, we identified CD84 as a kinase target of BTK, which is involved in granulopoiesis. In vitro, CD84 promoted alcohol-induced interleukin-1\u03b2 and tumor necrosis factor\u2013\u03b1 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.\n          <\/jats:p>","DOI":"10.1126\/scitranslmed.adg1915","type":"journal-article","created":{"date-parts":[[2024,8,7]],"date-time":"2024-08-07T18:02:45Z","timestamp":1723053765000},"update-policy":"https:\/\/doi.org\/10.34133\/aaas_crossmark","source":"Crossref","is-referenced-by-count":8,"title":["In vivo Bruton\u2019s tyrosine kinase inhibition attenuates alcohol-associated liver disease by regulating CD84-mediated granulopoiesis"],"prefix":"10.1126","volume":"16","author":[{"given":"Prashanth Thevkar","family":"Nagesh","sequence":"first","affiliation":[{"name":"Department of Medicine, Division of Gastroenterology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, 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