title: Pneumocystis infection alters the activation state of pulmonary macrophages.
abstract: Recent studies show a substantial incidence of Pneumocystis jirovecii colonization and infection in patients with chronic inflammatory lung conditions. However, little is known about the impact of Pneumocystis upon the regulation of pulmonary immunity. We demonstrate here that Pneumocystis polarizes macrophages towards an alternatively activated macrophage-like phenotype. Genetically engineered mice that lack the ability to signal through IL-4 and IL-13 were used to show that Pneumocystis alternative macrophage activation is dependent upon signaling through these cytokines. To determine whether Pneumocystis-induced macrophage polarization would impact subsequent immune responses, we infected mice with Pneumocystis and then challenged them with Pseudomonas aeruginosa 14 days later. In co-infected animals, a higher proportion of macrophages in the alveolar and interstitial spaces expressed both classical and alternatively activated markers and produced the regulatory cytokines TGFβ and IL-10, as well as higher arginase levels than in mice infected with P. aeruginosa alone. Our results suggest that Pneumocystis reprograms the overall macrophage repertoire in the lung to that of a more alternatively-activated setpoint, thereby altering subsequent immune responses. These data may help to explain the association between Pneumocystis infection and decline in pulmonary function.
authors.affiliation: Department of Microbiology, Immunology, and Molecular Genetics, University of Kentucky College of Medicine, 800 Rose Street Rm MS409, Lexington, KY 40536, USA.
authors.forename: Jessica M
authors.initials: JM
authors.lastname: Deckman
authors.affiliation: Department of Microbiology, Immunology, and Molecular Genetics, University of Kentucky College of Medicine, 800 Rose Street Rm MS409, Lexington, KY 40536, USA.
authors.forename: Cathryn J
authors.initials: CJ
authors.lastname: Kurkjian
authors.affiliation: Department of Microbiology, Immunology, and Molecular Genetics, University of Kentucky College of Medicine, 800 Rose Street Rm MS409, Lexington, KY 40536, USA.
authors.forename: Joseph P
authors.initials: JP
authors.lastname: McGillis
authors.affiliation: Department of Pharmacy Practice and Science, University of Kentucky College of Pharmacy, 789 S. Limestone Street Suite 292, Lexington, KY 40536, USA.
authors.forename: Theodore J
authors.initials: TJ
authors.lastname: Cory
authors.affiliation: Department of Pharmacy Practice and Science, University of Kentucky College of Pharmacy, 789 S. Limestone Street Suite 292, Lexington, KY 40536, USA.
authors.forename: Susan E
authors.initials: SE
authors.lastname: Birket
authors.affiliation: Department of Internal Medicine, University of Kentucky College of Medicine, 900 S. Limestone Street Suite 303, Lexington, KY 40536, USA.
authors.forename: Linda M
authors.initials: LM
authors.lastname: Schutzman
authors.affiliation: Department of Internal Medicine, University of Kentucky College of Medicine, 900 S. Limestone Street Suite 303, Lexington, KY 40536, USA.
authors.forename: Brian S
authors.initials: BS
authors.lastname: Murphy
authors.affiliation: Department of Microbiology, Immunology, and Molecular Genetics, University of Kentucky College of Medicine, 800 Rose Street Rm MS409, Lexington, KY 40536, USA.
authors.forename: Beth A
authors.initials: BA
authors.lastname: Garvy
authors.affiliation: Department of Pharmacy Practice and Science, University of Kentucky College of Pharmacy, 789 S. Limestone Street Suite 292, Lexington, KY 40536, USA. Electronic address: djfeol2@email.uky.edu.
authors.forename: David J
authors.initials: DJ
authors.lastname: Feola
mesh_terms: D000818:Animals; D015415:Biomarkers; D016207:Cytokines / Q000378:metabolism; D004195:Disease Models, Animal; D016130:Immunophenotyping; D008262:Macrophage Activation / Q000276:immunology; D016676:Macrophages, Alveolar / Q000276:immunology* / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D010641:Phenotype; D016720:Pneumocystis Infections / Q000235:genetics / Q000276:immunology* / Q000378:metabolism* / Q000382:microbiology; D045363:Pneumocystis carinii / Q000276:immunology; D018410:Pneumonia, Bacterial / Q000235:genetics / Q000276:immunology / Q000378:metabolism / Q000382:microbiology; D011956:Receptors, Cell Surface / Q000172:deficiency / Q000235:genetics; D053662:Interleukin-4 Receptor alpha Subunit
chemical_list: D015415:Biomarkers; D016207:Cytokines; D011956:Receptors, Cell Surface; C504002:Il4ra protein, mouse; D053662:Interleukin-4 Receptor alpha Subunit
keywords: Arginase; Inflammation; Macrophage; Pneumocystis