title: High-dosage granulocyte colony stimulating factor treatment alters monocyte trafficking to the brain after experimental stroke.
abstract: Ischemic stroke elicits a prompt inflammatory response that is characterized by a well-timed recruitment of peripheral immune cells to the brain. Among these, monocytes play a particularly important, but multifaceted role and have been increasingly recognized to affect stroke outcome. Granulocyte colony stimulating factor (GCSF) is known for its immunosuppressive actions on mononuclear cells, but previous studies in the stroke field were mainly confined to its neuroprotective actions. Herein, we investigated whether GCSF affects post-stroke inflammation in a mouse model of focal brain ischemia by modulating monocyte responses. Treatment with GCSF was controlled by vehicle injection, sham surgery and naive animals. Despite a significant monocytosis, high-dosage GCSF reduced the number of brain-infiltrating monocytes/macrophages four days after stroke. Lower numbers of mononuclear phagocytes in the brain were associated with smaller cerebral edema and improved motor outcome after stroke. GCSF treatment over 72h, but not 24h diminished integrin expression on circulating Ly6C+ inflammatory monocytes. In vitro experiments further revealed that GCSF strongly promotes interleukin (IL)-10 secretion by activated mononuclear cells. Blockade of the IL-10 receptor partly reversed GCSF-induced downregulation of integrin surface expression. Overall, our results suggest that high-dosage GCSF mitigates monocyte infiltration after stroke, likely by attenuating integrin-mediated adhesion to the brain endothelium in an IL-10-dependent manner. Lower amounts of mononuclear cells in the brain translate to less severe brain edema and functional impairment and thus support a harmful role of Ly6C+ inflammatory monocytes in the acute stage of stroke.
authors.affiliation: Fraunhofer Institute for Cell Therapy and Immunology, Leipzig, Germany; University of Leipzig, Department of Neurology, Leipzig, Germany. Electronic address: gesa.weise@izi.fraunhofer.de.
authors.forename: Gesa
authors.initials: G
authors.lastname: Weise
authors.affiliation: Fraunhofer Institute for Cell Therapy and Immunology, Leipzig, Germany.
authors.forename: Claudia
authors.initials: C
authors.lastname: Pösel
authors.affiliation: Fraunhofer Institute for Cell Therapy and Immunology, Leipzig, Germany.
authors.forename: Karoline
authors.initials: K
authors.lastname: Möller
authors.affiliation: Fraunhofer Institute for Cell Therapy and Immunology, Leipzig, Germany.
authors.forename: Alexander
authors.initials: A
authors.lastname: Kranz
authors.affiliation: Fraunhofer Institute for Cell Therapy and Immunology, Leipzig, Germany; Institute for Biology, Human Biology, University of Leipzig, Leipzig, Germany.
authors.forename: Nadine
authors.initials: N
authors.lastname: Didwischus
authors.affiliation: Fraunhofer Institute for Cell Therapy and Immunology, Leipzig, Germany; Fraunhofer Research Institution of Marine Biotechnology and Institute for Medical and Marine Biotechnology, University of Lübeck, Lübeck, Germany; Massachusetts General Hospital and Harvard Medical School, Stroke and Neurovascular Regulation Laboratory, Charlestown, MA, USA.
authors.forename: Johannes
authors.initials: J
authors.lastname: Boltze
authors.affiliation: Fraunhofer Institute for Cell Therapy and Immunology, Leipzig, Germany; Institute of Pathology, University Medical Center Mainz, Germany.
authors.forename: Daniel-Christoph
authors.initials: DC
authors.lastname: Wagner
mesh_terms: D000818:Animals; D001921:Brain / Q000187:drug effects* / Q000378:metabolism; D001929:Brain Edema / Q000188:drug therapy; D002545:Brain Ischemia / Q000188:drug therapy* / Q000378:metabolism; D002465:Cell Movement / Q000187:drug effects*; D004195:Disease Models, Animal; D016179:Granulocyte Colony-Stimulating Factor / Q000008:administration & dosage / Q000494:pharmacology*; D007249:Inflammation / Q000188:drug therapy / Q000378:metabolism; D008297:Male; D008810:Mice, Inbred C57BL; D009000:Monocytes / Q000187:drug effects* / Q000378:metabolism
chemical_list: D016179:Granulocyte Colony-Stimulating Factor
keywords: Cerebral stroke; Granulocyte colony stimulating factor; Inflammation; Leukocyte adhesion; Monocytes