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Cited by 40Neutrophil, Myeloperoxidase and Oxidative MechanismsCell death mechanisms and regulationPhagocytosis and Immune Regulation

Serum and glucocorticoid-regulated kinase 1 regulates neutrophil clearance during inflammation resolution

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Burgon, Joseph, Robertson, Anne L, Sadiku, Pranvera, Wang, Xingang, Hooper-Greenhill, Edward, Prince, Lynne R, Walker, Paul, Hoggett, Emily E +9 more·2014·The Journal of Immunology
DOI 10.4049/jimmunol.1300087PMC PMC3921102
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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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  • Inhibiting SGK activity completely nullifies effects of neutrophil survival factors, leading to delayed resolution of inflammation, but does not alter neutrophil recruitment to sites of inflammation.

    “Inhibiting SGK activity completely nullifies the effects of neutrophil survival factors, leading to a delayed resolution of inflammation. However, this does not alter the recruitment of neutrophils to sites of inflammation within the body”

    From Serum/glucocorticoid regulated kinase 1 (SGK1) in neurological disorders: pain or gain (2024) · cites this paper as Burgon et al., 2014

    The Results report that SGK1 inhibition increased, rather than delayed, inflammation resolution (genetic inhibition section; page unavailable). They also report that inhibition blocked survival induced by GM-CSF and hypoxia, but not by LPS or ATPγs (human neutrophil survival section). Recruitment was unchanged after genetic knockdown, although the inhibitor GSK650394 reduced it through apparent off-target effects. (LLM, conf=0.92)

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References 56 · Cited by 40

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Authors
Burgon, J., Robertson, A. L., Sadiku, P., Wang, X., Hooper-Greenhill, E., Prince, L. R., Walker, P., Hoggett, E. E., Ward, J. R., Farrow, S. N., Zuercher, W. J., Jeffrey, P., Savage, C. O., Ingham, P. W., Hurlstone, A. F., Whyte, M. K. B., & Renshaw, S. A.
Affiliations
  • Medical Research Council (GB)
  • University of Sheffield (GB)
  • Institute of Molecular and Cell Biology (SG)
  • Immuno-Inflammation Therapy Area Unit, GlaxoSmithKline Research and Development , Stevenage SG1 2NY,
  • University of Manchester (GB)
  • GlaxoSmithKline (United Kingdom) (GB)
  • GlaxoSmithKline (United States) (US)
Corresponding author
Burgon, Joseph
ORCID
Venue
The Journal of Immunology
Publisher
Oxford University Press (OUP)
Published
2014-02
Volume
192
Issue
4
Pages
1796-1805
ISSN
  • 0022-1767 (ISSN-L)
  • 1550-6606
DOI
10.4049/jimmunol.1300087
PMC
PMC3921102
OpenAlex
W2140341966
Cited by
40
References
56
Citations by year
2025: 6 · 2024: 5 · 2023: 2 · 2022: 2 · 2021: 3 · 2020: 2 · 2019: 5 · 2018: 3 · 2017: 1 · 2016: 6 · 2015: 3 · 2014: 2
FWCI
1.83
Type
journal article
Language
en
Open access
Licence
academic.oup.com/pages/standard-publication-reuse-rights (vor)
Locations
  • The Journal of Immunology (publishedVersion)
  • PubMed (publishedVersion)
  • Research Explorer (The University of Manchester) (publishedVersion)
  • Europe PMC (PubMed Central) (acceptedVersion)
  • PubMed Central (acceptedVersion)
Funders
  • Wellcome Trust (GR077544AIA)
  • Medical Research Council (MR/K006312/1, GR077544AIA, G0701932, G0700091)
Topics
  • Life Sciences › Immunology and Microbiology › Immunology › Neutrophil, Myeloperoxidase and Oxidative Mechanisms
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Cell death mechanisms and regulation
  • Life Sciences › Immunology and Microbiology › Immunology › Phagocytosis and Immune Regulation
Keywords
SGK1, neutrophil clearance, inflammation resolution, neutrophil apoptosis, GM-CSF, anti-inflammatory agents, phagocytosis
MeSH terms
Phosphoinositide-3 Kinase Inhibitors, Serum-Glucocorticoid Regulated Kinases, Animals, Benzoates, Cell Movement, Cell Survival, Humans, Inflammation, Neutrophils, RNA, Messenger, Zebrafish, Granulocyte-Macrophage Colony-Stimulating Factor, Apoptosis, Protein Serine-Threonine Kinases, Immediate-Early Proteins, Bridged Bicyclo Compounds, Heterocyclic, Phosphatidylinositol 3-Kinases, Animals, Genetically Modified, Morpholinos

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