title: Constitutive neutrophil apoptosis: regulation by cell concentration via S100 A8/9 and the MEK-ERK pathway.
abstract: 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.
authors.affiliation: The Laboratory for Cellular and Molecular Immunology, Department of Medicine, Hadassah-Hebrew University Medical Center Jerusalem, Jerusalem, Israel.
authors.forename: Mizhir
authors.initials: M
authors.lastname: Atallah
authors.forename: Alon
authors.initials: A
authors.lastname: Krispin
authors.forename: Uriel
authors.initials: U
authors.lastname: Trahtemberg
authors.forename: Sandrine
authors.initials: S
authors.lastname: Ben-Hamron
authors.forename: Amir
authors.initials: A
authors.lastname: Grau
authors.forename: Inna
authors.initials: I
authors.lastname: Verbovetski
authors.forename: Dror
authors.initials: D
authors.lastname: Mevorach
mesh_terms: D000595:Amino Acid Sequence; D017209:Apoptosis; D051017:Apoptosis Regulatory Proteins / Q000378:metabolism; D018821:CD18 Antigens / Q000378:metabolism; D040501:Calgranulin A / Q000737:chemistry / Q000378:metabolism*; D040502:Calgranulin B / Q000737:chemistry / Q000378:metabolism*; D002452:Cell Count; D002470:Cell Survival; D006801:Humans; D020935:MAP Kinase Signaling System; D013058:Mass Spectrometry; D008969:Molecular Sequence Data; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D018375:Neutrophil Activation; D009504:Neutrophils / Q000166:cytology* / Q000201:enzymology*; D040901:Proteomics; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D013347:Subcellular Fractions / Q000378:metabolism; D051197:Toll-Like Receptor 4 / Q000378:metabolism
chemical_list: D051017:Apoptosis Regulatory Proteins; D018821:CD18 Antigens; D040501:Calgranulin A; D040502:Calgranulin B; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D019253:Proto-Oncogene Proteins c-bcl-2; C495345:TLR4 protein, human; D051197:Toll-Like Receptor 4