دورية أكاديمية
BTK inhibitor-induced defects in human neutrophil effector activity against Aspergillus fumigatus are restored by TNF-α.
| العنوان: | BTK inhibitor-induced defects in human neutrophil effector activity against Aspergillus fumigatus are restored by TNF-α. |
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| المؤلفون: | Vargas-Blanco DA; Division of Infectious Diseases, Department of Medicine, Massachusetts General Hospital, Boston, Massachusetts, USA.; Harvard Medical School, Boston, Massachusetts, USA., Hepworth OW; Division of Infectious Diseases, Department of Medicine, Massachusetts General Hospital, Boston, Massachusetts, USA.; Harvard Medical School, Boston, Massachusetts, USA., Basham KJ; Division of Infectious Diseases, Department of Medicine, Massachusetts General Hospital, Boston, Massachusetts, USA., Simaku P; Division of Infectious Diseases, Department of Medicine, Massachusetts General Hospital, Boston, Massachusetts, USA., Crossen AJ; Division of Infectious Diseases, Department of Medicine, Massachusetts General Hospital, Boston, Massachusetts, USA., Timmer KD; Division of Infectious Diseases, Department of Medicine, Massachusetts General Hospital, Boston, Massachusetts, USA., Hopke A; Harvard Medical School, Boston, Massachusetts, USA.; BioMEMS Resource Center, Massachusetts General Hospital, Boston, Massachusetts, USA.; Shriners Hospital for Children, Boston, Massachusetts, USA., Brown Harding H; Division of Infectious Diseases, Department of Medicine, Massachusetts General Hospital, Boston, Massachusetts, USA.; Harvard Medical School, Boston, Massachusetts, USA., Vandal SR; Beth Israel Deaconess Medical Center, Boston, Massachusetts, USA., Jensen KN; Division of Infectious Diseases, Department of Medicine, Massachusetts General Hospital, Boston, Massachusetts, USA.; Harvard Medical School, Boston, Massachusetts, USA., Floyd DJ; Division of Infectious Diseases, Department of Medicine, Massachusetts General Hospital, Boston, Massachusetts, USA., Reedy JL; Division of Infectious Diseases, Department of Medicine, Massachusetts General Hospital, Boston, Massachusetts, USA.; Harvard Medical School, Boston, Massachusetts, USA., Reardon C; Division of Infectious Diseases, Department of Medicine, Massachusetts General Hospital, Boston, Massachusetts, USA., Mansour MK; Division of Infectious Diseases, Department of Medicine, Massachusetts General Hospital, Boston, Massachusetts, USA.; Harvard Medical School, Boston, Massachusetts, USA., Ward RA; Division of Infectious Diseases, Department of Medicine, Massachusetts General Hospital, Boston, Massachusetts, USA., Irimia D; Harvard Medical School, Boston, Massachusetts, USA.; BioMEMS Resource Center, Massachusetts General Hospital, Boston, Massachusetts, USA.; Shriners Hospital for Children, Boston, Massachusetts, USA., Abramson JS; Center for Lymphoma, Mass General Cancer Center, Boston, Massachusetts, USA., Vyas JM; Division of Infectious Diseases, Department of Medicine, Massachusetts General Hospital, Boston, Massachusetts, USA.; Harvard Medical School, Boston, Massachusetts, USA. |
| المصدر: | JCI insight [JCI Insight] 2024 May 07; Vol. 9 (12). Date of Electronic Publication: 2024 May 07. |
| نوع المنشور: | Journal Article |
| اللغة: | English |
| بيانات الدورية: | Publisher: American Society for Clinical Investigation Country of Publication: United States NLM ID: 101676073 Publication Model: Electronic Cited Medium: Internet ISSN: 2379-3708 (Electronic) Linking ISSN: 23793708 NLM ISO Abbreviation: JCI Insight Subsets: MEDLINE |
| أسماء مطبوعة: | Original Publication: Ann Arbor, Michigan : American Society for Clinical Investigation, [2016]- |
| مواضيع طبية MeSH: | Aspergillus fumigatus*/immunology , Neutrophils*/drug effects , Neutrophils*/immunology , Neutrophils*/metabolism , Tumor Necrosis Factor-alpha*/metabolism , Agammaglobulinaemia Tyrosine Kinase*/antagonists & inhibitors , Agammaglobulinaemia Tyrosine Kinase*/metabolism , Piperidines*/pharmacology , Reactive Oxygen Species*/metabolism , Adenine*/analogs & derivatives , Adenine*/pharmacology, Humans ; Aspergillosis/drug therapy ; Aspergillosis/immunology ; Pyrimidines/pharmacology ; Phagocytosis/drug effects ; Protein Kinase Inhibitors/pharmacology ; Signal Transduction/drug effects ; Pyrazoles/pharmacology |
| مستخلص: | Inhibition of Bruton's tyrosine kinase (BTK) through covalent modifications of its active site (e.g., ibrutinib [IBT]) is a preferred treatment for multiple B cell malignancies. However, IBT-treated patients are more susceptible to invasive fungal infections, although the mechanism is poorly understood. Neutrophils are the primary line of defense against these infections; therefore, we examined the effect of IBT on primary human neutrophil effector activity against Aspergillus fumigatus. IBT significantly impaired the ability of neutrophils to kill A. fumigatus and potently inhibited reactive oxygen species (ROS) production, chemotaxis, and phagocytosis. Importantly, exogenous TNF-α fully compensated for defects imposed by IBT and newer-generation BTK inhibitors and restored the ability of neutrophils to contain A. fumigatus hyphal growth. Blocking TNF-α did not affect ROS production in healthy neutrophils but prevented exogenous TNF-α from rescuing the phenotype of IBT-treated neutrophils. The restorative capacity of TNF-α was independent of transcription. Moreover, the addition of TNF-α immediately rescued ROS production in IBT-treated neutrophils, indicating that TNF-α worked through a BTK-independent signaling pathway. Finally, TNF-α restored effector activity of primary neutrophils from patients on IBT therapy. Altogether, our data indicate that TNF-α rescued the antifungal immunity block imposed by inhibition of BTK in primary human neutrophils. |
| فهرسة مساهمة: | Keywords: Cancer; Fungal infections; Immunology; Infectious disease; Neutrophils |
| المشرفين على المادة: | 0 (Tumor Necrosis Factor-alpha) EC 2.7.10.2 (Agammaglobulinaemia Tyrosine Kinase) 0 (Piperidines) 0 (Reactive Oxygen Species) JAC85A2161 (Adenine) EC 2.7.10.2 (BTK protein, human) 1X70OSD4VX (ibrutinib) 0 (Pyrimidines) 0 (Protein Kinase Inhibitors) 0 (Pyrazoles) |
| تواريخ الأحداث: | Date Created: 20240507 Date Completed: 20240624 Latest Revision: 20240711 |
| رمز التحديث: | 20240711 |
| DOI: | 10.1172/jci.insight.176162 |
| PMID: | 38713531 |
| قاعدة البيانات: | MEDLINE |
Full Text Finder | تدمد: | 2379-3708 |
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| DOI: | 10.1172/jci.insight.176162 |