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Exchange protein directly activated by cyclic AMP (EPAC) activation reverses neutrophil dysfunction induced by beta(2)-agonists, corticosteroids, and critical illness

Lookup NU author(s): Jonathan Scott, Dr Jim Macfarlane, Dr Tom Hellyer, Dr Anthony RostronORCiD, Dr Marie-Helene Ruchaud, Professor John SimpsonORCiD


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Background: Neutrophils play a role in the pathogenesis of asthma, chronic obstructive pulmonary disease, and pulmonary infection. Impaired neutrophil phagocytosis predicts hospital-acquired infection. Despite this, remarkably few neutrophil-specific treatments exist.Objectives: We sought to identify novel pathways for the restoration of effective neutrophil phagocytosis and to activate such pathways effectively in neutrophils from patients with impaired neutrophil phagocytosis.Methods: Blood neutrophils were isolated from healthy volunteers and patients with impaired neutrophil function. In healthy neutrophils phagocytic impairment was induced experimentally by using beta(2)-agonists. Inhibitors and activators of cyclic AMP (cAMP)-dependent pathways were used to assess the influence on neutrophil phagocytosis in vitro.Results: beta(2)-Agonists and corticosteroids inhibited neutrophil phagocytosis. Impairment of neutrophil phagocytosis by beta(2)-agonists was associated with significantly reduced RhoA activity. Inhibition of protein kinase A (PKA) restored phagocytosis and RhoA activity, suggesting that cAMP signals through PKA to drive phagocytic impairment. However, cAMP can signal through effectors other than PKA, such as exchange protein directly activated by cyclic AMP (EPAC). An EPAC-activating analog of cAMP (8CPT-2Me-cAMP) reversed neutrophil dysfunction induced by beta(2)-agonists or corticosteroids but did not increase RhoA activity. 8CPT-2Me-cAMP reversed phagocytic impairment induced by Rho kinase inhibition but was ineffective in the presence of Rap-1 GTPase inhibitors. 8CPT-2Me-cAMP restored function to neutrophils from patients with known acquired impairment of neutrophil phagocytosis.Conclusions: EPAC activation consistently reverses clinical and experimental impairment of neutrophil phagocytosis. EPAC signals through Rap-1 and bypasses RhoA. EPAC activation represents a novel potential means by which to reverse impaired neutrophil phagocytosis.

Publication metadata

Author(s): Scott J, Harris GJ, Pinder EM, Macfarlane JG, Hellyer TP, Rostron AJ, Morris AC, Thickett DR, Perkins GD, McAuley DF, Widdrington JD, Wiscombe S, Baudouin SV, Roy AI, Linnett VC, Wright SE, Ruchaud-Sparagano MH, Simpson AJ

Publication type: Article

Publication status: Published

Journal: Journal of Allergy and Clinical Immunology

Year: 2016

Volume: 137

Issue: 2

Pages: 535-544

Print publication date: 01/02/2016

Online publication date: 18/09/2015

Acceptance date: 14/07/2015

ISSN (print): 0091-6749

ISSN (electronic): 1097-6825

Publisher: Elsevier


DOI: 10.1016/j.jaci.2015.07.036


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