The Library
Exchange protein directly activated by cyclic AMP (EPAC) activation reverses neutrophil dysfunction induced by β2-agonists, corticosteroids, and critical illness
Tools
Tools
Tools
Scott, Jonathan, Harris, Graham J., Pinder, Emma M., Macfarlane, James G., Hellyer, Thomas P., Rostron, Anthony J., Conway Morris, Andrew, Thickett, David R., Perkins, Gavin D., McAuley, Daniel F., Widdrington, John D., Wiscombe, Sarah, Baudouin, Simon V., Roy, Alistair I., Linnett, Vanessa C., Wright, Stephen E., Ruchaud-Sparagano, Marie-Hélène and Simpson, A. John (2016) Exchange protein directly activated by cyclic AMP (EPAC) activation reverses neutrophil dysfunction induced by β2-agonists, corticosteroids, and critical illness. Journal of Allergy and Clinical Immunology , 137 (2). pp. 535-544. doi:10.1016/j.jaci.2015.07.036 ISSN 0091-6749.
Research output not available from this repository.
Request-a-Copy directly from author or use local Library Get it For Me service.
Official URL: http://dx.doi.org/10.1016/j.jaci.2015.07.036
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.
| Item Type: | Journal Article | ||||||||
|---|---|---|---|---|---|---|---|---|---|
| Divisions: | Faculty of Science, Engineering and Medicine > Medicine > Warwick Medical School > Clinical Trials Unit Faculty of Science, Engineering and Medicine > Medicine > Warwick Medical School > Health Sciences Faculty of Science, Engineering and Medicine > Medicine > Warwick Medical School |
||||||||
| Journal or Publication Title: | Journal of Allergy and Clinical Immunology | ||||||||
| Publisher: | Mosby, Inc. | ||||||||
| ISSN: | 0091-6749 | ||||||||
| Official Date: | February 2016 | ||||||||
| Dates: |
|
||||||||
| Volume: | 137 | ||||||||
| Number: | 2 | ||||||||
| Page Range: | pp. 535-544 | ||||||||
| DOI: | 10.1016/j.jaci.2015.07.036 | ||||||||
| Status: | Peer Reviewed | ||||||||
| Publication Status: | Published | ||||||||
| Access rights to Published version: | Restricted or Subscription Access |
Request changes or add full text files to a record
Repository staff actions (login required)
 |
View Item |
