title: Monocytic cell differentiation from band-stage neutrophils under inflammatory conditions via MKK6 activation.
abstract: During inflammation, neutrophils are rapidly mobilized from the bone marrow storage pool into peripheral blood (PB) to enter lesional sites, where most rapidly undergo apoptosis. Monocytes constitute a second wave of inflammatory immigrates, giving rise to long-lived macrophages and dendritic cell subsets. According to descriptive immunophenotypic and cell culture studies, neutrophils may directly "transdifferentiate" into monocytes/macrophages. We provide mechanistic data in human and murine models supporting the existence of this cellular pathway. First, the inflammatory signal-induced MKK6-p38MAPK cascade activates a monocyte differentiation program in human granulocyte colony-stimulating factor-dependent neutrophils. Second, adoptively transferred neutrophils isolated from G-CSF-pretreated mice rapidly acquired monocyte characteristics in response to inflammatory signals in vivo. Consistently, inflammatory signals led to the recruitment of osteoclast progenitor cell potential from ex vivo-isolated G-CSF-mobilized human blood neutrophils. Monocytic cell differentiation potential was retained in left-shifted band-stage neutrophils but lost in neutrophils from steady-state PB. MKK6-p38MAPK signaling in HL60 model cells led to diminishment of the transcription factor C/EBPα, which enabled the induction of a monocytic cell differentiation program. Gene profiling confirmed lineage conversion from band-stage neutrophils to monocytic cells. Therefore, inflammatory signals relayed by the MKK6-p38MAPK cascade induce monocytic cell differentiation from band-stage neutrophils.
authors.affiliation: Institute of Immunology, Center of Pathophysiology, Infectiology and Immunology, Medical University of Vienna, Vienna, Austria; Institute of Pathophysiology and Immunology, Center of Molecular Medicine, Medical University Graz, Graz, Austria;
authors.forename: René
authors.initials: R
authors.lastname: Köffel
authors.affiliation: Institute of Immunology, Center of Pathophysiology, Infectiology and Immunology, Medical University of Vienna, Vienna, Austria;
authors.forename: Anastasia
authors.initials: A
authors.lastname: Meshcheryakova
authors.affiliation: Center of Excellence for Medical Multimedia (CeMM), Research Center for Molecular Medicine of the Austrian Academy of Sciences and Department of Internal Medicine I, Laboratory of Infection Biology, Medical University of Vienna, Vienna, Austria;
authors.forename: Joanna
authors.initials: J
authors.lastname: Warszawska
authors.affiliation: Institute of Immunology, Center of Pathophysiology, Infectiology and Immunology, Medical University of Vienna, Vienna, Austria;
authors.forename: Annika
authors.initials: A
authors.lastname: Hennig
authors.affiliation: Center for Medical Research, Medical University Graz, Graz, Austria;
authors.forename: Karin
authors.initials: K
authors.lastname: Wagner
authors.affiliation: Institute of Immunology, Center of Pathophysiology, Infectiology and Immunology, Medical University of Vienna, Vienna, Austria;
authors.forename: Almut
authors.initials: A
authors.lastname: Jörgl
authors.affiliation: Institute of Immunology, Center of Pathophysiology, Infectiology and Immunology, Medical University of Vienna, Vienna, Austria;
authors.forename: Daniela
authors.initials: D
authors.lastname: Gubi
authors.affiliation: Department of Craniofacial, Maxillofacial and Oral Surgery.
authors.forename: Doris
authors.initials: D
authors.lastname: Moser
authors.affiliation: Division of Rheumatology, Medicine III, and.
authors.forename: Anastasiya
authors.initials: A
authors.lastname: Hladik
authors.affiliation: Institute of Pathophysiology and Immunology, Center of Molecular Medicine, Medical University Graz, Graz, Austria;
authors.forename: Ulrike
authors.initials: U
authors.lastname: Hoffmann
authors.affiliation: Department of Blood Group Serology and Transfusion Medicine, Medical University of Vienna, Vienna, Austria; and.
authors.forename: Michael B
authors.initials: MB
authors.lastname: Fischer
authors.affiliation: Department of Rheumatology, Rheumatology Research and Advanced Therapeutics, Radboud University Nijmegen Medical Center, Nijmegen, The Netherlands.
authors.forename: Wim
authors.initials: W
authors.lastname: van den Berg
authors.affiliation: Department of Rheumatology, Rheumatology Research and Advanced Therapeutics, Radboud University Nijmegen Medical Center, Nijmegen, The Netherlands.
authors.forename: Marije
authors.initials: M
authors.lastname: Koenders
authors.affiliation: Division of Rheumatology, Medicine III, and.
authors.forename: Clemens
authors.initials: C
authors.lastname: Scheinecker
authors.affiliation: Institute of Immunology, Center of Pathophysiology, Infectiology and Immunology, Medical University of Vienna, Vienna, Austria;
authors.forename: Bernhard
authors.initials: B
authors.lastname: Gesslbauer
authors.affiliation: Center of Excellence for Medical Multimedia (CeMM), Research Center for Molecular Medicine of the Austrian Academy of Sciences and Department of Internal Medicine I, Laboratory of Infection Biology, Medical University of Vienna, Vienna, Austria;
authors.forename: Sylvia
authors.initials: S
authors.lastname: Knapp
authors.affiliation: Institute of Immunology, Center of Pathophysiology, Infectiology and Immunology, Medical University of Vienna, Vienna, Austria; Institute of Pathophysiology and Immunology, Center of Molecular Medicine, Medical University Graz, Graz, Austria;
authors.forename: Herbert
authors.initials: H
authors.lastname: Strobl
mesh_terms: D000818:Animals; D015153:Blotting, Western; D022763:CCAAT-Enhancer-Binding Protein-alpha / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D002454:Cell Differentiation / Q000187:drug effects / Q000235:genetics / Q000276:immunology*; D002478:Cells, Cultured; D004789:Enzyme Activation / Q000187:drug effects / Q000276:immunology; D005434:Flow Cytometry; D016179:Granulocyte Colony-Stimulating Factor / Q000494:pharmacology; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000494:pharmacology; D018922:HL-60 Cells; D006801:Humans; D007249:Inflammation / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D053583:Interleukin-1beta / Q000494:pharmacology; D048669:MAP Kinase Kinase 6 / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D008810:Mice, Inbred C57BL; D009000:Monocytes / Q000276:immunology* / Q000378:metabolism; D009504:Neutrophils / Q000276:immunology* / Q000378:metabolism; D020411:Oligonucleotide Array Sequence Analysis; D010006:Osteoblasts / Q000276:immunology / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics / Q000276:immunology; D059467:Transcriptome / Q000187:drug effects / Q000276:immunology; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology; D048051:p38 Mitogen-Activated Protein Kinases / Q000235:genetics / Q000276:immunology / Q000378:metabolism
chemical_list: D022763:CCAAT-Enhancer-Binding Protein-alpha; D053583:Interleukin-1beta; D014409:Tumor Necrosis Factor-alpha; D016179:Granulocyte Colony-Stimulating Factor; D016178:Granulocyte-Macrophage Colony-Stimulating Factor; D048051:p38 Mitogen-Activated Protein Kinases; D048669:MAP Kinase Kinase 6; C482566:MAP2K6 protein, human