| Autor: |
Nagesh, Prashanth Thevkar, Cho, Yeonhee, Zhuang, Yuan, Babuta, Mrigya, Ortega-Ribera, Marti, Joshi, Radhika, Brezani, Veronika, Patel, Arman, Datta, Aditi Ashish, Brezani, Viliam, Hsieh, Yun-Cheng, Ramos, Adriana, Mehta, Jeeval, Copeland, Christopher, Kanata, Eleni, Jiang, Zhenghui Gordon, Vlachos, Ioannis, Asara, John, Szabo, Gyongyi |
| Předmět: |
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| Zdroj: |
Science Translational Medicine; 8/7/2024, Vol. 16 Issue 759, p1-17, 17p |
| Abstrakt: |
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. Editor's summary: Alcoholic liver disease is uniquely characterized by the hepatic infiltration of neutrophils. Nagesh et al. now show that Bruton's tyrosine kinase (BTK) is involved in this altered neutrophil homeostasis. Studying mouse models of alcohol-associated hepatitis, they found that BTK directly interacted with CD84 to promote bone marrow granulopoiesis and the inflammatory neutrophil infiltration that drives subsequent liver injury, particularly after alcohol binge. Pharmacological BTK inhibition reduced proinflammatory cytokines and attenuated neutrophil-mediated liver damage in a mouse model of alcohol-associated hepatitis. BTK activation was also found to be increased in patients with alcohol-associated hepatitis, indicating translational relevance of the identified mechanism of alcohol-induced liver injury. —Catherine Charneski [ABSTRACT FROM AUTHOR] |
| Databáze: |
Complementary Index |
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