Constitutive neutrophil apoptosis: regulation by cell concentration via S100 A8/9 and the MEK-ERK pathway

PLoS One. 2012;7(2):e29333. doi: 10.1371/journal.pone.0029333. Epub 2012 Feb 17.


Programmed cell death (PCD) is a fundamental mechanism in tissue and cell homeostasis. It was long suggested that apoptosis regulates the cell number in diverse cell populations; however no clear mechanism was shown. Neutrophils are the short-lived, first-line defense of innate immunity, with an estimated t = 1/2 of 8 hours and a high turnover rate. Here we first show that spontaneous neutrophil constitutive PCD is regulated by cell concentrations. Using a proteomic approach, we identified the S100 A8/9 complex, which constitutes roughly 40% of cytosolic protein in neutrophils, as mediating this effect. We further demonstrate that it regulates cell survival via a signaling mechanism involving MEK-ERK via TLR4 and CD11B/CD18. This mechanism is suggested to have a fine-tuning role in regulating the neutrophil number in bone marrow, peripheral blood, and inflammatory sites.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Sequence
  • Apoptosis Regulatory Proteins / metabolism
  • Apoptosis*
  • CD18 Antigens / metabolism
  • Calgranulin A / chemistry
  • Calgranulin A / metabolism*
  • Calgranulin B / chemistry
  • Calgranulin B / metabolism*
  • Cell Count
  • Cell Survival
  • Humans
  • MAP Kinase Signaling System*
  • Mass Spectrometry
  • Molecular Sequence Data
  • Myeloid Cell Leukemia Sequence 1 Protein
  • Neutrophil Activation
  • Neutrophils / cytology*
  • Neutrophils / enzymology*
  • Proteomics
  • Proto-Oncogene Proteins c-bcl-2 / metabolism
  • Subcellular Fractions / metabolism
  • Toll-Like Receptor 4 / metabolism


  • Apoptosis Regulatory Proteins
  • CD18 Antigens
  • Calgranulin A
  • Calgranulin B
  • Myeloid Cell Leukemia Sequence 1 Protein
  • Proto-Oncogene Proteins c-bcl-2
  • TLR4 protein, human
  • Toll-Like Receptor 4