title: Paradoxical role of alveolar macrophage-derived granulocyte-macrophage colony-stimulating factor in pulmonary host defense post-bone marrow transplantation.
abstract: Impaired host defense post-bone marrow transplant (BMT) is related to overproduction of prostaglandin E(2) (PGE(2)) by alveolar macrophages (AMs). We show AMs post-BMT overproduce granulocyte-macrophage colony-stimulating factor (GM-CSF), whereas GM-CSF in lung homogenates is impaired both at baseline and in response to infection post-BMT. Homeostatic regulation of GM-CSF may occur by hematopoietic/structural cell cross talk. To determine whether AM overproduction of GM-CSF influenced immunosuppression post-BMT, we compared mice that received BMT from wild-type donors (control BMT) or mice that received BMT from GM-CSF-/- donors (GM-CSF-/- BMT) with untransplanted mice. GM-CSF-/- BMT mice were less susceptible to pneumonia with Pseudomonas aeruginosa compared with control BMT mice and showed antibacterial responses equal to or better than untransplanted mice. GM-CSF-/- BMT AMs displayed normal phagocytosis and a trend toward enhanced bacterial killing. Surprisingly, AMs from GM-CSF-/- BMT mice overproduced PGE(2), but expression of the inhibitory EP(2) receptor was diminished. As a consequence of decreased EP(2) receptor expression, we found diminished accumulation of cAMP in response to PGE(2) stimulation in GM-CSF-/- BMT AMs compared with control BMT AMs. In addition, GM-CSF-/- BMT AMs retained cysteinyl leukotriene production and normal TNF-alpha response compared with AMs from control BMT mice. GM-CSF-/- BMT neutrophils also showed improved bacterial killing. Although genetic ablation of GM-CSF in hematopoietic cells post-BMT improved host defense, transplantation of wild-type bone marrow into GM-CSF-/- recipients demonstrated that parenchymal cell-derived GM-CSF is necessary for effective innate immune responses post-BMT. These results highlight the complex regulation of GM-CSF and innate immunity post-BMT.
authors.affiliation: The Department of Internal Medicine, Division of Pulmonary and Critical Care Medicine, University of Michigan, Ann Arbor, Michigan 48109-2200, USA.
authors.forename: Megan N
authors.initials: MN
authors.lastname: Ballinger
authors.forename: Leah L N
authors.initials: LL
authors.lastname: Hubbard
authors.forename: Tracy R
authors.initials: TR
authors.lastname: McMillan
authors.forename: Galen B
authors.initials: GB
authors.lastname: Toews
authors.forename: Marc
authors.initials: M
authors.lastname: Peters-Golden
authors.forename: Robert
authors.initials: R
authors.lastname: Paine
authors.forename: Bethany B
authors.initials: BB
authors.lastname: Moore
mesh_terms: D000818:Animals; D016026:Bone Marrow Transplantation; D015232:Dinoprostone / Q000276:immunology; D005786:Gene Expression Regulation / Q000235:genetics / Q000276:immunology; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000235:genetics / Q000276:immunology*; D006412:Hematopoietic Stem Cells / Q000276:immunology / Q000473:pathology; D007113:Immunity, Innate / Q000235:genetics; D016676:Macrophages, Alveolar / Q000276:immunology* / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D009504:Neutrophils / Q000276:immunology / Q000473:pathology; D010587:Phagocytosis / Q000235:genetics / Q000276:immunology; D018410:Pneumonia, Bacterial / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D011552:Pseudomonas Infections / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D011550:Pseudomonas aeruginosa / Q000276:immunology*; D018078:Receptors, Prostaglandin E / Q000235:genetics / Q000276:immunology; D058307:Receptors, Prostaglandin E, EP2 Subtype
chemical_list: C545645:Ptger2 protein, mouse; D018078:Receptors, Prostaglandin E; D058307:Receptors, Prostaglandin E, EP2 Subtype; D016178:Granulocyte-Macrophage Colony-Stimulating Factor; D015232:Dinoprostone