title: Serum and glucocorticoid-regulated kinase 1 regulates neutrophil clearance during inflammation resolution.
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.
authors.affiliation: Medical Research Council Centre for Developmental and Biomedical Genetics, University of Sheffield, Sheffield S10 2TN, United Kingdom;
authors.forename: Joseph
authors.initials: J
authors.lastname: Burgon
authors.forename: Anne L
authors.initials: AL
authors.lastname: Robertson
authors.forename: Pranvera
authors.initials: P
authors.lastname: Sadiku
authors.forename: Xingang
authors.initials: X
authors.lastname: Wang
authors.forename: Edward
authors.initials: E
authors.lastname: Hooper-Greenhill
authors.forename: Lynne R
authors.initials: LR
authors.lastname: Prince
authors.forename: Paul
authors.initials: P
authors.lastname: Walker
authors.forename: Emily E
authors.initials: EE
authors.lastname: Hoggett
authors.forename: Jonathan R
authors.initials: JR
authors.lastname: Ward
authors.forename: Stuart N
authors.initials: SN
authors.lastname: Farrow
authors.forename: William J
authors.initials: WJ
authors.lastname: Zuercher
authors.forename: Philip
authors.initials: P
authors.lastname: Jeffrey
authors.forename: Caroline O
authors.initials: CO
authors.lastname: Savage
authors.forename: Philip W
authors.initials: PW
authors.lastname: Ingham
authors.forename: Adam F
authors.initials: AF
authors.lastname: Hurlstone
authors.forename: Moira K B
authors.initials: MK
authors.lastname: Whyte
authors.forename: Stephen A
authors.initials: SA
authors.lastname: Renshaw
mesh_terms: D000818:Animals; D030801:Animals, Genetically Modified; D017209:Apoptosis / Q000276:immunology*; D001565:Benzoates / Q000494:pharmacology; D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000494:pharmacology; D002465:Cell Movement / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects / Q000276:immunology; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000378:metabolism*; D006801:Humans; D017874:Immediate-Early Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D007249:Inflammation / Q000276:immunology*; D060172:Morpholinos / Q000235:genetics; D009504:Neutrophils / Q000187:drug effects / Q000276:immunology*; D019869:Phosphatidylinositol 3-Kinases / Q000187:drug effects; D000081082:Phosphoinositide-3 Kinase Inhibitors; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D012333:RNA, Messenger / Q000096:biosynthesis; D015027:Zebrafish / Q000235:genetics; D000099184:Serum-Glucocorticoid Regulated Kinases
chemical_list: D001565:Benzoates; D019086:Bridged Bicyclo Compounds, Heterocyclic; D016178:Granulocyte-Macrophage Colony-Stimulating Factor; D017874:Immediate-Early Proteins; D060172:Morpholinos; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D017346:Protein Serine-Threonine Kinases; D012333:RNA, Messenger; D000099184:Serum-Glucocorticoid Regulated Kinases; C532254:2-cyclopentyl-4-(5-phenyl-1H-pyrrolo(2,3-b)pyridin-3-yl)-benzoic acid