Go to JCI Insight
  • About
  • Editors
  • Consulting Editors
  • For authors
  • Publication ethics
  • Publication alerts by email
  • Advertising
  • Job board
  • Contact
  • Clinical Research and Public Health
  • Current issue
  • Past issues
  • By specialty
    • COVID-19
    • Cardiology
    • Gastroenterology
    • Immunology
    • Metabolism
    • Nephrology
    • Neuroscience
    • Oncology
    • Pulmonology
    • Vascular biology
    • All ...
  • Videos
    • Conversations with Giants in Medicine
    • Video Abstracts
  • Reviews
    • View all reviews ...
    • Complement Biology and Therapeutics (May 2025)
    • Evolving insights into MASLD and MASH pathogenesis and treatment (Apr 2025)
    • Microbiome in Health and Disease (Feb 2025)
    • Substance Use Disorders (Oct 2024)
    • Clonal Hematopoiesis (Oct 2024)
    • Sex Differences in Medicine (Sep 2024)
    • Vascular Malformations (Apr 2024)
    • View all review series ...
  • Viewpoint
  • Collections
    • In-Press Preview
    • Clinical Research and Public Health
    • Research Letters
    • Letters to the Editor
    • Editorials
    • Commentaries
    • Editor's notes
    • Reviews
    • Viewpoints
    • 100th anniversary
    • Top read articles

  • Current issue
  • Past issues
  • Specialties
  • Reviews
  • Review series
  • Conversations with Giants in Medicine
  • Video Abstracts
  • In-Press Preview
  • Clinical Research and Public Health
  • Research Letters
  • Letters to the Editor
  • Editorials
  • Commentaries
  • Editor's notes
  • Reviews
  • Viewpoints
  • 100th anniversary
  • Top read articles
  • About
  • Editors
  • Consulting Editors
  • For authors
  • Publication ethics
  • Publication alerts by email
  • Advertising
  • Job board
  • Contact
BTK drives neutrophil activation for sterilizing antifungal immunity
Jigar V. Desai, … , Tobias M. Hohl, Michail S. Lionakis
Jigar V. Desai, … , Tobias M. Hohl, Michail S. Lionakis
Published May 2, 2024
Citation Information: J Clin Invest. 2024;134(12):e176142. https://doi.org/10.1172/JCI176142.
View: Text | PDF
Research Article Immunology Infectious disease Article has an altmetric score of 44

BTK drives neutrophil activation for sterilizing antifungal immunity

  • Text
  • PDF
Abstract

We describe a previously unappreciated role for Bruton’s tyrosine kinase (BTK) in fungal immune surveillance against aspergillosis, an unforeseen complication of BTK inhibitors (BTKi) used for treating B cell lymphoid malignancies. We studied BTK-dependent fungal responses in neutrophils from diverse populations, including healthy donors, patients who were treated with BTKi, and X-linked agammaglobulinemia patients. Upon fungal exposure, BTK was activated in human neutrophils in a TLR2-, Dectin-1-, and FcγR-dependent manner, triggering the oxidative burst. BTK inhibition selectively impeded neutrophil-mediated damage to Aspergillus hyphae, primary granule release, and the fungus-induced oxidative burst by abrogating NADPH oxidase subunit p40phox and GTPase RAC2 activation. Moreover, neutrophil-specific Btk deletion in mice enhanced aspergillosis susceptibility by impairing neutrophil function, not recruitment or lifespan. Conversely, GM-CSF partially mitigated these deficits by enhancing p47phox activation. Our findings underline the crucial role of BTK signaling in neutrophils for antifungal immunity and provide a rationale for GM-CSF use to offset these deficits in patients who are susceptible.

Authors

Jigar V. Desai, Marissa A. Zarakas, Andrew L. Wishart, Mark Roschewski, Mariano A. Aufiero, Agnes Donkò, Gustaf Wigerblad, Neta Shlezinger, Markus Plate, Matthew R. James, Jean K. Lim, Gulbu Uzel, Jenna R.E. Bergerson, Ivan Fuss, Robert A. Cramer, Luis M. Franco, Emily S. Clark, Wasif N. Khan, Daisuke Yamanaka, Georgios Chamilos, Jamel El-Benna, Mariana J. Kaplan, Louis M. Staudt, Thomas L. Leto, Steven M. Holland, Wyndham H. Wilson, Tobias M. Hohl, Michail S. Lionakis

×

Figure 3

BTK inhibition in vivo, in patients with lymphoma, reduces neutrophil hyphal damage, oxidative burst, and primary granule release.

Options: View larger image (or click on image) Download as PowerPoint
BTK inhibition in vivo, in patients with lymphoma, reduces neutrophil hy...
(A) Schematic outline depicting treatment with BTKi (ibrutinib or acalabrutinib) and the timepoints of blood collection for neutrophil isolation in patients with lymphoma. (B–G) Neutrophils were isolated from patients with lymphoma before and at day 3 after treatment initiation of ibrutinib (n = 7-9) or acalabrutinib (n = 4-6). Each dot represents an individual patient. (B) A. fumigatus hyphal damage induced by neutrophils (effector:target ratio, 8:1) (n = 6). (C and D) Representative FACS histograms (C) and MFI summary data (D) depicting dihydrorhodamine 123 oxidation to rhodamine in neutrophils stimulated as indicated (ibrutinib, n = 8; acalabrutinib, n = 5). (E and F) Luminol-amplified chemiluminescence. Temporal chemiluminescence RLU trace (E) and AUC for RLU (F) of neutrophils upon stimulation as indicated (ibrutinib, n = 9; acalabrutinib, n = 4). (G) Patient neutrophils were coincubated with A. fumigatus hyphae (effector:target ratio, 8:1) and the indicated granule components were analyzed via ELISA in the supernatants of neutrophil-hyphal cocultures (ibrutinib, n = 7-8; acalabrutinib, n = 6). (H) Gene ontology (GO) terms of downregulated genes in neutrophils from patients with lymphoma isolated at day 3 after acalabrutinib treatment relative to baseline, using pseudo-bulk processing of single-cell transcriptomes (n = 3). (I) A. fumigatus hyphal damage induced by neutrophils isolated from patients with lymphoma at the indicated timepoints (effector:target ratio, 8:1). Except for panel I, each dot represents an individual patient. For panel I, data are from 3 patients, with 6 technical replicates per patient, where each dot represents a technical replicate, and quantitative data are means ± SEM. BTKi, BTK inhibitor; MPO: myeloperoxidase; MMP-9: Matrix metalloproteinase-9; PMA, phorbol-12-myristate-13-acetate; Af: Aspergillus fumigatus; HK Af: heat-killed Aspergillus fumigatus. *P<0.05, **P<0.01, ***P<0.001 using Kruskal-Wallis test with Dunn’s multiple comparisons test (I), or paired t test (B, D, F, and G).

Copyright © 2025 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)

Sign up for email alerts

Picked up by 1 news outlets
Blogged by 1
Posted by 50 X users
On 1 Facebook pages
24 readers on Mendeley
See more details