Serum and Glucocorticoid–Regulated Kinase 1 Regulates Neutrophil Clearance during Inflammation Resolution Joseph Burgon, Anne L. Robertson, Pranvera Sadiku, Xingang Wang, Edward Hooper-Greenhill, Lynne R. Prince, Paul Walker, Emily E. Hoggett, Jonathan R. Ward, Stuart N. Farrow, William J. Zuercher, Philip Jeffrey, Caroline O. Savage, Philip W. Ingham, Adam F. Hurlstone, Moira K. B. Whyte, and Stephen A. Renshaw J Immunol 2014 192:1796-1805; published ahead of print January 15, 2014, doi:10.4049/jimmunol.1300087
Abstract:
The inflammatory response is integral to maintaining health by functioning to resist microbial infection and repair tissue damage. Large numbers of neutrophils are recruited to inflammatory sites to neutralize invading bacteria through phagocytosis and the release of proteases and reactive oxygen species into the extracellular environment. Removal of the original inflammatory stimulus must be accompanied by resolution of the inflammatory response, including neutrophil clearance, to prevent inadvertent tissue damage. Neutrophil apoptosis and its temporary inhibition by survival signals provides a target for anti-inflammatory therapeutics, making it essential to better understand this process. GM-CSF, a neutrophil survival factor, causes a significant increase in mRNA levels for the known anti-apoptotic protein serum and glucocorticoid–regulated kinase 1 (SGK1). We have characterized the expression patterns and regulation of SGK family members in human neutrophils and shown that inhibition of SGK activity completely abrogates the antiapoptotic effect of GM-CSF. Using a transgenic zebrafish model, we have disrupted sgk1 gene function and shown this specifically delays inflammation resolution, without altering neutrophil recruitment to inflammatory sites in vivo. These data suggest SGK1 plays a key role in regulating neutrophil survival signaling and thus may prove a valuable therapeutic target for the treatment of inflammatory disease.
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Funding Info:
This work was supported by Medical Research Council Senior Clinical Fellowship Grant G0701932 (to S.A.R.) and Medical Research Council Centre Grant G0700091. Microscopy studies were supported by Wellcome Trust Grant GR077544AIA to the Molecular Biology and Biotechnology/Biomedical Science Light Microscopy Facility.
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