Exchange protein directly activated by cyclic AMP (EPAC) activation reverses neutrophil dysfunction induced by β2-agonists, corticosteroids, and critical illness

Jonathan Scott, Graham J. Harris, Emma M. Pinder, James G. Macfarlane, Thomas P. Hellyer, Anthony J. Rostron, Andrew Conway Morris, David R. Thickett, Gavin D. Perkins, Daniel F. McAuley, John D. Widdrington, Sarah Wiscombe, Simon V. Baudouin, Alistair I. Roy, Vanessa C. Linnett, Stephen E. Wright, Marie Hélène Ruchaud-Sparagano, A. John Simpson*

*Corresponding author for this work

Research output: Contribution to journalArticle

15 Citations (Scopus)

Abstract

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 β2-agonists. Inhibitors and activators of cyclic AMP (cAMP)-dependent pathways were used to assess the influence on neutrophil phagocytosis in vitro. 

Results β2-Agonists and corticosteroids inhibited neutrophil phagocytosis. Impairment of neutrophil phagocytosis by β2-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 β2-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.

Original languageEnglish
Pages (from-to)535-544
Number of pages10
JournalThe Journal of allergy and clinical immunology
Volume137
Issue number2
Early online date18 Sep 2015
DOIs
Publication statusPublished - 01 Feb 2016

Keywords

  • cyclic AMP
  • exchange protein directly activated by cyclic AMP
  • hospital-acquired infection
  • Neutrophil
  • β-agonist

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

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    Scott, J., Harris, G. J., Pinder, E. M., Macfarlane, J. G., Hellyer, T. P., Rostron, A. J., Conway Morris, A., Thickett, D. R., Perkins, G. D., McAuley, D. F., Widdrington, J. D., Wiscombe, S., Baudouin, S. V., Roy, A. I., Linnett, V. C., Wright, S. E., Ruchaud-Sparagano, M. H., & Simpson, A. J. (2016). Exchange protein directly activated by cyclic AMP (EPAC) activation reverses neutrophil dysfunction induced by β2-agonists, corticosteroids, and critical illness. The Journal of allergy and clinical immunology, 137(2), 535-544. https://doi.org/10.1016/j.jaci.2015.07.036