title: G-CSF maintains controlled neutrophil mobilization during acute inflammation by negatively regulating CXCR2 signaling.
abstract: Cytokine-induced neutrophil mobilization from the bone marrow to circulation is a critical event in acute inflammation, but how it is accurately controlled remains poorly understood. In this study, we report that CXCR2 ligands are responsible for rapid neutrophil mobilization during early-stage acute inflammation. Nevertheless, although serum CXCR2 ligand concentrations increased during inflammation, neutrophil mobilization slowed after an initial acute fast phase, suggesting a suppression of neutrophil response to CXCR2 ligands after the acute phase. We demonstrate that granulocyte colony-stimulating factor (G-CSF), usually considered a prototypical neutrophil-mobilizing cytokine, was expressed later in the acute inflammatory response and unexpectedly impeded CXCR2-induced neutrophil mobilization by negatively regulating CXCR2-mediated intracellular signaling. Blocking G-CSF in vivo paradoxically elevated peripheral blood neutrophil counts in mice injected intraperitoneally with Escherichia coli and sequestered large numbers of neutrophils in the lungs, leading to sterile pulmonary inflammation. In a lipopolysaccharide-induced acute lung injury model, the homeostatic imbalance caused by G-CSF blockade enhanced neutrophil accumulation, edema, and inflammation in the lungs and ultimately led to significant lung damage. Thus, physiologically produced G-CSF not only acts as a neutrophil mobilizer at the relatively late stage of acute inflammation, but also prevents exaggerated neutrophil mobilization and the associated inflammation-induced tissue damage during early-phase infection and inflammation.
authors.affiliation: Department of Pathology, Harvard Medical School, Boston, MA 02115 Department of Lab Medicine, The Stem Cell Program, Joint Program in Transfusion Medicine, Children's Hospital Boston, Boston, MA 02115 Dana-Farber/Harvard Cancer Center, Boston, MA 02115.
authors.forename: Besnik
authors.initials: B
authors.lastname: Bajrami
authors.affiliation: The State Key Laboratory of Experimental Hematology, Institute of Hematology and Blood Diseases Hospital, Center for Stem Cell Medicine, Chinese Academy of Medical Sciences and Peking Union Medical College, Tianjin 300020, China.
authors.forename: Haiyan
authors.initials: H
authors.lastname: Zhu
authors.affiliation: Department of Pathology, Harvard Medical School, Boston, MA 02115 Department of Lab Medicine, The Stem Cell Program, Joint Program in Transfusion Medicine, Children's Hospital Boston, Boston, MA 02115 Dana-Farber/Harvard Cancer Center, Boston, MA 02115.
authors.forename: Hyun-Jeong
authors.identifier: 0000-0001-7070-6066
authors.initials: HJ
authors.lastname: Kwak
authors.affiliation: Department of Pathology, Harvard Medical School, Boston, MA 02115 Department of Lab Medicine, The Stem Cell Program, Joint Program in Transfusion Medicine, Children's Hospital Boston, Boston, MA 02115 Dana-Farber/Harvard Cancer Center, Boston, MA 02115.
authors.forename: Subhanjan
authors.identifier: 0000-0002-4852-0369
authors.initials: S
authors.lastname: Mondal
authors.affiliation: Department of Pathology, Harvard Medical School, Boston, MA 02115 Department of Lab Medicine, The Stem Cell Program, Joint Program in Transfusion Medicine, Children's Hospital Boston, Boston, MA 02115 Dana-Farber/Harvard Cancer Center, Boston, MA 02115.
authors.forename: Qingming
authors.identifier: 0000-0002-8805-2053
authors.initials: Q
authors.lastname: Hou
authors.affiliation: The State Key Laboratory of Experimental Hematology, Institute of Hematology and Blood Diseases Hospital, Center for Stem Cell Medicine, Chinese Academy of Medical Sciences and Peking Union Medical College, Tianjin 300020, China.
authors.forename: Guangfeng
authors.identifier: 0000-0002-0518-406X
authors.initials: G
authors.lastname: Geng
authors.affiliation: Department of Pathology, Harvard Medical School, Boston, MA 02115 Department of Lab Medicine, The Stem Cell Program, Joint Program in Transfusion Medicine, Children's Hospital Boston, Boston, MA 02115 Dana-Farber/Harvard Cancer Center, Boston, MA 02115.
authors.forename: Kutay
authors.identifier: 0000-0003-0555-8225
authors.initials: K
authors.lastname: Karatepe
authors.affiliation: Department of Pathology, Harvard Medical School, Boston, MA 02115 Department of Lab Medicine, The Stem Cell Program, Joint Program in Transfusion Medicine, Children's Hospital Boston, Boston, MA 02115 Dana-Farber/Harvard Cancer Center, Boston, MA 02115.
authors.forename: Yu C
authors.initials: YC
authors.lastname: Zhang
authors.affiliation: Department of Pathology, Harvard Medical School, Boston, MA 02115 Department of Lab Medicine, The Stem Cell Program, Joint Program in Transfusion Medicine, Children's Hospital Boston, Boston, MA 02115 Dana-Farber/Harvard Cancer Center, Boston, MA 02115 Department of Experimental Hematology, University Hospital Zurich, 8091 Zurich, Switzerland.
authors.forename: César
authors.identifier: 0000-0003-0415-259X
authors.initials: C
authors.lastname: Nombela-Arrieta
authors.affiliation: Department of Pathology, Harvard Medical School, Boston, MA 02115 Department of Lab Medicine, The Stem Cell Program, Joint Program in Transfusion Medicine, Children's Hospital Boston, Boston, MA 02115 Dana-Farber/Harvard Cancer Center, Boston, MA 02115.
authors.forename: Shin-Young
authors.identifier: 0000-0001-6385-4132
authors.initials: SY
authors.lastname: Park
authors.affiliation: Department of Pathology, Harvard Medical School, Boston, MA 02115 Department of Lab Medicine, The Stem Cell Program, Joint Program in Transfusion Medicine, Children's Hospital Boston, Boston, MA 02115 Dana-Farber/Harvard Cancer Center, Boston, MA 02115.
authors.forename: Fabien
authors.identifier: 0000-0002-6678-1730
authors.initials: F
authors.lastname: Loison
authors.affiliation: Department of Pathology, Harvard Medical School, Boston, MA 02115 Department of Lab Medicine, The Stem Cell Program, Joint Program in Transfusion Medicine, Children's Hospital Boston, Boston, MA 02115 Dana-Farber/Harvard Cancer Center, Boston, MA 02115.
authors.forename: Jiro
authors.identifier: 0000-0002-2526-2766
authors.initials: J
authors.lastname: Sakai
authors.affiliation: The State Key Laboratory of Experimental Hematology, Institute of Hematology and Blood Diseases Hospital, Center for Stem Cell Medicine, Chinese Academy of Medical Sciences and Peking Union Medical College, Tianjin 300020, China.
authors.forename: Yuanfu
authors.identifier: 0000-0003-0576-3907
authors.initials: Y
authors.lastname: Xu
authors.affiliation: Department of Pathology, Harvard Medical School, Boston, MA 02115 Department of Lab Medicine, The Stem Cell Program, Joint Program in Transfusion Medicine, Children's Hospital Boston, Boston, MA 02115 Dana-Farber/Harvard Cancer Center, Boston, MA 02115.
authors.forename: Leslie E
authors.identifier: 0000-0002-4624-0013
authors.initials: LE
authors.lastname: Silberstein
authors.affiliation: Department of Pathology, Harvard Medical School, Boston, MA 02115 Department of Lab Medicine, The Stem Cell Program, Joint Program in Transfusion Medicine, Children's Hospital Boston, Boston, MA 02115 Dana-Farber/Harvard Cancer Center, Boston, MA 02115 Hongbo.Luo@childrens.harvard.edu.
authors.forename: Hongbo R
authors.initials: HR
authors.lastname: Luo
mesh_terms: D000208:Acute Disease; D000818:Animals; D001853:Bone Marrow / Q000473:pathology; D054426:Chemokine CXCL2 / Q000378:metabolism; D002633:Chemotaxis; D004926:Escherichia coli / Q000502:physiology; D016179:Granulocyte Colony-Stimulating Factor / Q000378:metabolism*; D008024:Ligands; D008070:Lipopolysaccharides; D008168:Lung / Q000473:pathology; D055370:Lung Injury / Q000097:blood / Q000150:complications / Q000382:microbiology / Q000473:pathology; D008810:Mice, Inbred C57BL; D009504:Neutrophils / Q000473:pathology*; D011014:Pneumonia / Q000097:blood / Q000150:complications / Q000378:metabolism* / Q000473:pathology*; D023063:Receptors, Interleukin-8B / Q000378:metabolism*; D050796:STAT3 Transcription Factor / Q000378:metabolism; D015398:Signal Transduction
chemical_list: D054426:Chemokine CXCL2; C404915:Cxcl2 protein, mouse; D008024:Ligands; D008070:Lipopolysaccharides; D023063:Receptors, Interleukin-8B; D050796:STAT3 Transcription Factor; D016179:Granulocyte Colony-Stimulating Factor