BTK drives neutrophil activation for sterilizing antifungal immunity Journal Article
| Authors: | Desai, J. V.; Zarakas, M. A.; Wishart, A. L.; Roschewski, M.; Aufiero, M. A.; Donkò, A.; Wigerblad, G.; Shlezinger, N.; Plate, M.; James, M. R.; Lim, J. K.; Uzel, G.; Bergerson, J. R. E.; Fuss, I.; Cramer, R. A.; Franco, L. M.; Clark, E. S.; Khan, W. N.; Yamanaka, D.; Chamilos, G.; El-Benna, J.; Kaplan, M. J.; Staudt, L. M.; Leto, T. L.; Holland, S. M.; Wilson, W. H.; Hohl, T. M.; Lionakis, M. S. |
| Article Title: | BTK drives neutrophil activation for sterilizing antifungal immunity |
| 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. © 2024, Desai et al. |
| Journal Title: | Journal of Clinical Investigation |
| Volume: | 134 |
| Issue: | 12 |
| ISSN: | 0021-9738 |
| Publisher: | American Society for Clinical Investigation |
| Date Published: | 2024-06-17 |
| Start Page: | e176142 |
| Language: | English |
| DOI: | 10.1172/jci176142 |
| PUBMED: | 38696257 |
| PROVIDER: | scopus |
| PMCID: | PMC11178547 |
| DOI/URL: | |
| Notes: | Article -- MSK Cancer Center Support Grant (P30 CA008748) acknowledged in PubMed and PDF -- Source: Scopus |
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