title: Endothelial cells translate pathogen signals into G-CSF-driven emergency granulopoiesis.
abstract: Systemic bacterial infection induces a hematopoietic response program termed "emergency granulopoiesis" that is characterized by increased de novo bone marrow (BM) neutrophil production. How loss of local immune control and bacterial dissemination is sensed and subsequently translated into the switch from steady-state to emergency granulopoiesis is, however, unknown. Using tissue-specific myeloid differentiation primary response gene 88 (Myd88)-deficient mice and in vivo lipopolysaccharide (LPS) administration to model severe bacterial infection, we here show that endothelial cells (ECs) but not hematopoietic cells, hepatocytes, pericytes, or BM stromal cells, are essential cells for this process. Indeed, ECs from multiple tissues including BM express high levels of Tlr4 and Myd88 and are the primary source of granulocyte colony-stimulating factor (G-CSF), the key granulopoietic cytokine, after LPS challenge or infection with Escherichia coli. EC-intrinsic MYD88 signaling and subsequent G-CSF production by ECs is required for myeloid progenitor lineage skewing toward granulocyte-macrophage progenitors, increased colony-forming unit granulocyte activity in BM, and accelerated BM neutrophil generation after LPS stimulation. Thus, ECs catalyze the detection of systemic infection into demand-adapted granulopoiesis.
authors.affiliation: Division of Hematology, University Hospital Zurich, Zurich, Switzerland;
authors.forename: Steffen
authors.initials: S
authors.lastname: Boettcher
authors.affiliation: Division of Hematology, University Hospital Zurich, Zurich, Switzerland;
authors.forename: Rahel C
authors.initials: RC
authors.lastname: Gerosa
authors.affiliation: Division of Hematology, University Hospital Zurich, Zurich, Switzerland;
authors.forename: Ramin
authors.initials: R
authors.lastname: Radpour
authors.affiliation: Institute for Virology, Technical University Munich/Helmholtz Center Munich, Munich, Germany; and.
authors.forename: Judith
authors.initials: J
authors.lastname: Bauer
authors.affiliation: Institute for Molecular Health Sciences, Molecular Biomedicine, Swiss Federal Institute of Technology Zurich, Zurich, Switzerland.
authors.forename: Franziska
authors.initials: F
authors.lastname: Ampenberger
authors.affiliation: Institute for Virology, Technical University Munich/Helmholtz Center Munich, Munich, Germany; and.
authors.forename: Mathias
authors.initials: M
authors.lastname: Heikenwalder
authors.affiliation: Institute for Molecular Health Sciences, Molecular Biomedicine, Swiss Federal Institute of Technology Zurich, Zurich, Switzerland.
authors.forename: Manfred
authors.initials: M
authors.lastname: Kopf
authors.affiliation: Division of Hematology, University Hospital Zurich, Zurich, Switzerland;
authors.forename: Markus G
authors.initials: MG
authors.lastname: Manz
mesh_terms: D000818:Animals; D003114:Colony-Forming Units Assay; D042783:Endothelial Cells / Q000502:physiology*; D004927:Escherichia coli Infections / Q000473:pathology / Q000503:physiopathology; D016179:Granulocyte Colony-Stimulating Factor / Q000502:physiology*; D006098:Granulocytes / Q000473:pathology* / Q000502:physiology*; D054884:Host-Pathogen Interactions / Q000502:physiology*; D008070:Lipopolysaccharides / Q000008:administration & dosage; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D008954:Models, Biological; D053594:Myeloid Differentiation Factor 88 / Q000172:deficiency / Q000235:genetics / Q000502:physiology; D038042:Myelopoiesis / Q000502:physiology*; D009504:Neutrophils / Q000473:pathology / Q000502:physiology; D015398:Signal Transduction; D051197:Toll-Like Receptor 4 / Q000172:deficiency / Q000235:genetics / Q000502:physiology; D019010:Vascular Cell Adhesion Molecule-1 / Q000502:physiology
chemical_list: D008070:Lipopolysaccharides; C507780:Myd88 protein, mouse; D053594:Myeloid Differentiation Factor 88; C493487:Tlr4 protein, mouse; D051197:Toll-Like Receptor 4; D019010:Vascular Cell Adhesion Molecule-1; D016179:Granulocyte Colony-Stimulating Factor