NR4A orphan nuclear receptor family members, NR4A2 and NR4A3, regulate neutrophil number and survival

Prince, L.R., Dannewitz Prosseda, S., Higgins, K., Carlring, J., Prestwich, E.C., Ogryzko, N.V., Rahman, A., Basran, A., Falciani, F., Taylor, P., Renshaw, S.A., Whyte, M.K.B., Sabroe, I.
Blood   130(8): 1014-1025 (Journal)
Registered Authors
Ogryzko, Nikolay, Renshaw, Steve A.
MeSH Terms
  • Animals
  • Cell Count
  • Cell Proliferation
  • Cell Survival
  • Cyclic AMP-Dependent Protein Kinases/metabolism
  • Dinoprostone/metabolism
  • Enzyme Activation
  • Gene Deletion
  • Gene Knockdown Techniques
  • Humans
  • Inflammation/pathology
  • Larva/metabolism
  • Mice
  • Multigene Family
  • Neutrophils/cytology*
  • Neutrophils/metabolism*
  • Nuclear Receptor Subfamily 4, Group A, Member 2/metabolism*
  • Nuclear Receptor Subfamily 4, Group A, Member 3/metabolism*
  • Oligonucleotide Array Sequence Analysis
  • RNA, Messenger/genetics
  • RNA, Messenger/metabolism
  • RNA, Small Interfering/metabolism
  • Real-Time Polymerase Chain Reaction
  • Reproducibility of Results
  • Signal Transduction
  • Transcription, Genetic
  • Zebrafish/metabolism*
28637666 Full text @ Blood
The lifespan of neutrophils is plastic and highly responsive to factors that regulate cellular survival. Defects in neutrophil number and survival are common to both hematologic disorders and chronic inflammatory diseases. At sites of inflammation, neutrophils respond to multiple signals that activate protein kinase A (PKA) signaling, which positively regulates neutrophil survival. The aim of this study was to define transcriptional responses to PKA activation and to delineate the roles of these factors in neutrophil function and survival. In human neutrophil gene array studies, we show that PKA activation upregulates a significant number of apoptosis-related genes, the most highly regulated of these being NR4A2 and NR4A3 Direct PKA activation by the site-selective PKA agonist pair N6/8-AHA (8-AHA-cAMP and N6-MB-cAMP) and treatment with endogenous activators of PKA, including adenosine and prostaglandin E2, results in a profound delay of neutrophil apoptosis and concomitant upregulation of NR4A2/3 in a PKA-dependent manner. NR4A3 expression is also increased at sites of neutrophilic inflammation in a human model of intradermal inflammation. PKA activation also promotes survival of murine neutrophil progenitor cells, and small interfering RNA to NR4A2 decreases neutrophil production in this model. Antisense knockdown of NR4A2 and NR4A3 homologs in zebrafish larvae significantly reduces the absolute neutrophil number without affecting cellular migration. In summary, we show that NR4A2 and NR4A3 are components of a downstream transcriptional response to PKA activation in the neutrophil, and that they positively regulate neutrophil survival and homeostasis.
Genes / Markers
Show all Figures
Mutation and Transgenics
Human Disease / Model Data
Sequence Targeting Reagents
Engineered Foreign Genes
Errata and Notes