title: GM-CSF modulates pulmonary resistance to influenza A infection.
abstract: Alveolar type II epithelial or other pulmonary cells secrete GM-CSF that regulates surfactant catabolism and mucosal host defense through its capacity to modulate the maturation and activation of alveolar macrophages. GM-CSF enhances expression of scavenger receptors MARCO and SR-A. The alveolar macrophage SP-R210 receptor binds the surfactant collectin SP-A mediating clearance of respiratory pathogens. The current study determined the effects of epithelial-derived GM-CSF in host resistance to influenza A pneumonia. The results demonstrate that GM-CSF enhanced resistance to infection with 1.9×10(4) ffc of the mouse-adapted influenza A/Puerto Rico/8/34 (PR8) H1N1 strain, as indicated by significant differences in mortality and mean survival of GM-CSF-deficient (GM(-/-)) mice compared to GM(-/-) mice in which GM-CSF is expressed at increased levels. Protective effects of GM-CSF were observed both in mice with constitutive and inducible GM-CSF expression under the control of the pulmonary-specific SFTPC or SCGB1A1 promoters, respectively. Mice that continuously secrete high levels of GM-CSF developed desquamative interstitial pneumonia that impaired long-term recovery from influenza. Conditional expression of optimal GM-CSF levels at the time of infection, however, resulted in alveolar macrophage proliferation and focal lymphocytic inflammation of distal airways. GM-CSF enhanced alveolar macrophage activity as indicated by increased expression of SP-R210 and CD11c. Infection of mice lacking the GM-CSF-regulated SR-A and MARCO receptors revealed that MARCO decreases resistance to influenza in association with increased levels of SP-R210 in MARCO(-/-) alveolar macrophages. In conclusion, GM-CSF enhances early host resistance to influenza. Targeting of MARCO may reinforce GM-CSF-mediated host defense against pathogenic influenza.
authors.affiliation: University of Texas Health Science Center at Tyler, Center of Biomedical Research, 11937 US HWY 271, Tyler, TX 75708-3154, United States.
authors.forename: Zvjezdana
authors.initials: Z
authors.lastname: Sever-Chroneos
authors.forename: Aditi
authors.initials: A
authors.lastname: Murthy
authors.forename: Jeremy
authors.initials: J
authors.lastname: Davis
authors.forename: Jon Matthew
authors.initials: JM
authors.lastname: Florence
authors.forename: Anna
authors.initials: A
authors.lastname: Kurdowska
authors.forename: Agnieszka
authors.initials: A
authors.lastname: Krupa
authors.forename: Jay W
authors.initials: JW
authors.lastname: Tichelaar
authors.forename: Mitchell R
authors.initials: MR
authors.lastname: White
authors.forename: Kevan L
authors.initials: KL
authors.lastname: Hartshorn
authors.forename: Lester
authors.initials: L
authors.lastname: Kobzik
authors.forename: Jeffrey A
authors.initials: JA
authors.lastname: Whitsett
authors.forename: Zissis C
authors.initials: ZC
authors.lastname: Chroneos
mesh_terms: D000818:Animals; D005260:Female; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000276:immunology*; D053118:Influenza A Virus, H1N1 Subtype / Q000276:immunology* / Q000472:pathogenicity*; D008168:Lung / Q000276:immunology / Q000473:pathology; D008214:Lymphocytes / Q000276:immunology; D008264:Macrophages / Q000276:immunology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009976:Orthomyxoviridae Infections / Q000401:mortality / Q000473:pathology / Q000517:prevention & control*; D016019:Survival Analysis
chemical_list: D016178:Granulocyte-Macrophage Colony-Stimulating Factor