title: M-CSF Mediates Host Defense during Bacterial Pneumonia by Promoting the Survival of Lung and Liver Mononuclear Phagocytes.
abstract: Gram-negative bacterial pneumonia is a common and dangerous infection with diminishing treatment options due to increasing antibiotic resistance among causal pathogens. The mononuclear phagocyte system is a heterogeneous group of leukocytes composed of tissue-resident macrophages, dendritic cells, and monocyte-derived cells that are critical in defense against pneumonia, but mechanisms that regulate their maintenance and function during infection are poorly defined. M-CSF has myriad effects on mononuclear phagocytes but its role in pneumonia is unknown. We therefore tested the hypothesis that M-CSF is required for mononuclear phagocyte-mediated host defenses during bacterial pneumonia in a murine model of infection. Genetic deletion or immunoneutralization of M-CSF resulted in reduced survival, increased bacterial burden, and greater lung injury. M-CSF was necessary for the expansion of lung mononuclear phagocytes during infection but did not affect the number of bone marrow or blood monocytes, proliferation of precursors, or recruitment of leukocytes to the lungs. In contrast, M-CSF was essential to survival and antimicrobial functions of both lung and liver mononuclear phagocytes during pneumonia, and its absence resulted in bacterial dissemination to the liver and hepatic necrosis. We conclude that M-CSF is critical to host defenses against bacterial pneumonia by mediating survival and antimicrobial functions of mononuclear phagocytes in the lungs and liver.
authors.affiliation: Department of Microbiology, Immunology, and Cancer Biology, University of Virginia, Charlottesville, VA 22908;
authors.forename: Alexandra
authors.initials: A
authors.lastname: Bettina
authors.affiliation: Division of Pulmonary and Critical Care, Department of Medicine, University of Virginia, Charlottesville, VA 22908;
authors.forename: Zhimin
authors.initials: Z
authors.lastname: Zhang
authors.affiliation: Department of Microbiology, Immunology, and Cancer Biology, University of Virginia, Charlottesville, VA 22908;
authors.forename: Kathryn
authors.initials: K
authors.lastname: Michels
authors.affiliation: Division of Pulmonary and Critical Care, Department of Medicine, University of Virginia, Charlottesville, VA 22908;
authors.forename: R Elaine
authors.initials: RE
authors.lastname: Cagnina
authors.affiliation: Division of Nephrology, Department of Medicine, University of Virginia, Charlottesville, VA 22908;
authors.forename: Isaah S
authors.initials: IS
authors.lastname: Vincent
authors.affiliation: Division of Pulmonary and Critical Care, Department of Medicine, University of Virginia, Charlottesville, VA 22908;
authors.forename: Marie D
authors.initials: MD
authors.lastname: Burdick
authors.affiliation: Division of Pulmonary and Critical Care, Department of Medicine, University of Virginia, Charlottesville, VA 22908; Department of Pharmacology, University of Virginia, Charlottesville, VA 22908; and.
authors.forename: Alexandra
authors.identifier: 0000-0001-6285-574X
authors.initials: A
authors.lastname: Kadl
authors.affiliation: Department of Microbiology, Immunology, and Cancer Biology, University of Virginia, Charlottesville, VA 22908; Division of Pulmonary and Critical Care, Department of Medicine, University of Virginia, Charlottesville, VA 22908; Beirne B. Carter Center for Immunology, University of Virginia, Charlottesville, VA 22908 mehrad@virginia.edu.
authors.forename: Borna
authors.initials: B
authors.lastname: Mehrad
mesh_terms: D000818:Animals; D057134:Antibodies, Neutralizing / Q000008:administration & dosage / Q000276:immunology; D001853:Bone Marrow / Q000276:immunology; D001854:Bone Marrow Cells / Q000187:drug effects / Q000276:immunology; D007710:Klebsiella Infections / Q000276:immunology* / Q000382:microbiology; D007711:Klebsiella pneumoniae / Q000276:immunology; D008099:Liver / Q000166:cytology / Q000276:immunology* / Q000382:microbiology / Q000473:pathology; D008168:Lung / Q000166:cytology / Q000276:immunology* / Q000382:microbiology / Q000473:pathology; D016173:Macrophage Colony-Stimulating Factor / Q000172:deficiency / Q000235:genetics / Q000276:immunology* / Q000494:pharmacology; D051379:Mice; D009000:Monocytes / Q000276:immunology / Q000382:microbiology; D012157:Mononuclear Phagocyte System / Q000276:immunology*; D010586:Phagocytes / Q000276:immunology*; D018410:Pneumonia, Bacterial / Q000276:immunology* / Q000382:microbiology
chemical_list: D057134:Antibodies, Neutralizing; D016173:Macrophage Colony-Stimulating Factor