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Phosphoinositide 3-kinase δ inhibition improves neutrophil bacterial killing in critically ill patients at high risk of infection

Lookup NU author(s): Dr Marie Ruchaud-Sparagano, Dr Kate Musgrave, Dr Stephen Wright, Dr John Perry, Dr Anthony Rostron, Professor John Simpson

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Abstract

© 2021 by TheAmericanAssociation of Immunologists, Inc.Acquired neutrophil dysfunction frequently develops during critical illness, independently increasing the risk for intensive care Unit-acquired infection. PI3Kδ is implicated in driving neutrophil dysfunction and can potentially be targeted pharmacologically. The aims of this study were to determine whether PI3Kδ inhibition reverses dysfunction in neutrophils from critically ill patients and to describe potential mechanisms. Neutrophils were isolated from blood taken from critically ill patients requiring intubation and mechanical ventilation, renal support, or blood pressure support. In separate validation experiments, neutrophil dysfunction was induced pharmacologically in neutrophils from healthy volunteers. Phagocytosis and bacterial killing assays were performed, and activity of RhoA and protein kinase A (PKA) was assessed. Inhibitors of PI3Kδ, 3-phosphoinositide-dependent protein kinase-1 (PDK1), and PKA were used to determine mechanisms of neutrophil dysfunction. Sixty-six patients were recruited. In the 27 patients (40.9%) with impaired neutrophil function, PI3Kd inhibition consistently improved function and significantly increased bacterial killing. These findings were validated in neutrophils from healthy volunteers with salbutamol-induced dysfunction and extended to demonstrate that PI3Kδ inhibition restored killing of clinical isolates of nine pathogens commonly associated with intensive care unit-acquired infection. PI3Kδ activation was associated with PDK1 activation, which in turn phosphorylated PKA, which drove phosphorylation and inhibition of the key regulator of neutrophil phagocytosis, RhoA. These data indicate that, in a significant proportion of critically ill patients, PI3Kδ inhibition can improve neutrophil function through PDK1- and PKA-dependent processes, suggesting that therapeutic use of PI3Kδ inhibitors warrants investigation in this setting.


Publication metadata

Author(s): Scott J, Ruchaud-Sparagano M-H, Musgrave K, Roy AI, Wright SE, Perry JD, Morris AC, Rostron AJ, Simpson AJ

Publication type: Article

Publication status: Published

Journal: Journal of Immunology

Year: 2021

Volume: 207

Issue: 7

Pages: 1776-1784

Online publication date: 20/09/2021

Acceptance date: 20/07/2021

ISSN (print): 0022-1767

ISSN (electronic): 1550-6606

Publisher: American Association of Immunologists

URL: https://doi.org/10.4049/jimmunol.2000603

DOI: 10.4049/jimmunol.2000603


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