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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.
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Research Article Immunology Infectious disease Article has an altmetric score of 44

BTK drives neutrophil activation for sterilizing antifungal immunity

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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

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Figure 7

GM-CSF rescues BTK-inhibited neutrophil functional defects and improves survival in Aspergillus-infected Btk–/– mice.

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GM-CSF rescues BTK-inhibited neutrophil functional defects and improves ...
(A–C) Luminol-amplified chemiluminescence. Representative relative light units (RLU) trace of ibrutinib-treated healthy donor neutrophils (A), and AUC for RLU in vehicle- or ibrutinib-treated healthy donor (B) or BTKi-treated lymphoma patient neutrophils (C), in response to 50 ng/mL (A) or increasing concentrations of GM-CSF (B and C). Each dot depicts an individual donor (B, n = 5; C, n = 3). (D and E) Representative immunoblot images (top) and pixel density (bottom) of p40phox (phospho-T154; D) and p47phox (phospho-S345; E) upon GM-CSF (50 ng/mL) treatment, in ibrutinib-treated, HK Af stimulated healthy donor neutrophils. (n = 7). (F–H) Neutrophils were isolated from a patient with XLA, at baseline, 2 hours, 5 weeks, and 8 weeks after GM-CSF treatment (500 μg, Sargramostim injection, 3× weekly). (F) Representative RLU trace at baseline and 2 hours after GM-CSF treatment initiation, upon stimulation as indicated. (G and H) A. fumigatus hyphal damage (G) and MPO release upon hyphal coincubation (H) (effector:target ratio, 8:1). Each dot represents a single donor (healthy donors; G and H), or a technical replicate (XLA patient; G). (I) Survival of GM-CSF or vehicle-treated Btk–/– mice after infection with A. fumigatus (n = 20). Ibrutinib concentration, 250 nM (A–C) or 2.5 μM (D and E). BTKi, BTK inhibitor; IBR, ibrutinib; XLA: X-linked agammaglobulinemia; GM-CSF: granulocyte-macrophage colony-stimulating factor; Af: Aspergillus fumigatus; HK Af: heat-killed Aspergillus fumigatus. Bars depict mean values (C and H). Box and whisker plots depict range from minimum to maximum (B and G). Dotted lines mark 25th and 75th percentile MPO values for healthy donor neutrophils (H). *P<0.05, **P<0.01, ***P<0.001, ****P<0.0001, determined using repeated measures 1-way ANOVA with Dunnett’s multiple comparisons test (B, live-Af; C), Friedman’s test with Dunn’s multiple comparison test (B, HK-Af), 2-sided paired t test (D, E, and G), Mann-Whitney U test (G), or log-rank test (I).

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ISSN: 0021-9738 (print), 1558-8238 (online)

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