title: Abrogation of IL-4 receptor-α-dependent alternatively activated macrophages is sufficient to confer resistance against pulmonary cryptococcosis despite an ongoing T(h)2 response.
abstract: In the murine model of pulmonary infection with Cryptococcus neoformans, IL-4 receptor α (IL-4Rα)-dependent polyfunctional T(h)2 cells induce disease progression associated with alternative activation of lung macrophages. To characterize the effector role of IL-4Rα-dependent alternatively activated macrophages (aaMph), we intra-nasally infected mice with genetically ablated IL-4Rα expression on macrophages (LysM(Cre)IL-4Rα(-/lox) mice) and IL-4Rα(-/lox) littermates. LysM(Cre)IL-4Rα(-/lox) mice were significantly more resistant to pulmonary cryptococcosis with higher survival rates and lower lung burden than non-deficient heterozygous littermates. Infected LysM(Cre)IL-4Rα(-/lox) mice had reduced but detectable numbers of aaMph expressing arginase-1, chitinase-like enzyme (YM1) and CD206. Similar pulmonary expression of inducible nitric oxide synthase was found in LysM(Cre)IL-4Rα(-/lox) and IL-4Rα(-/lox) control mice, but macrophages from LysM(Cre)IL-4Rα(-/lox) mice showed a higher potential to produce nitric oxide. In contrast to the differences in the macrophage phenotype, pulmonary T(h)2 responses were similar in infected LysM(Cre)IL-4Rα(-/lox) and IL-4Rα(-/lox) mice with each mouse strain harboring polyfunctional T(h)2 cells. Consistently, type 2 pulmonary allergic inflammation associated with eosinophil recruitment and epithelial mucus production was present in lungs of both LysM(Cre)IL-4Rα(-/lox) and IL-4Rα(-/lox) mice. Our results demonstrate that, despite residual IL-4Rα-independent alternative macrophage activation and ongoing T(h)2-dependent allergic inflammation, abrogation of IL-4Rα-dependent aaMph is sufficient to confer resistance in pulmonary cryptococcosis. This is even evident on a relatively resistant heterozygous IL-4Rα(+/-) background indicating a key contribution of macrophage IL-4Rα expression to susceptibility in allergic bronchopulmonary mycosis.
authors.affiliation: Institute of Immunology/Molecular Pathogenesis, Center for Biotechnology and Biomedicine, College of Veterinary Medicine, University of Leipzig, Germany.
authors.forename: Uwe
authors.initials: U
authors.lastname: Müller
authors.forename: Werner
authors.initials: W
authors.lastname: Stenzel
authors.forename: Daniel
authors.initials: D
authors.lastname: Piehler
authors.forename: Andreas
authors.initials: A
authors.lastname: Grahnert
authors.forename: Martina
authors.initials: M
authors.lastname: Protschka
authors.forename: Gabriele
authors.initials: G
authors.lastname: Köhler
authors.forename: Oliver
authors.initials: O
authors.lastname: Frey
authors.forename: Josephin
authors.initials: J
authors.lastname: Held
authors.forename: Tina
authors.initials: T
authors.lastname: Richter
authors.forename: Maria
authors.initials: M
authors.lastname: Eschke
authors.forename: Thomas
authors.initials: T
authors.lastname: Kamradt
authors.forename: Frank
authors.initials: F
authors.lastname: Brombacher
authors.forename: Gottfried
authors.initials: G
authors.lastname: Alber
mesh_terms: D000818:Animals; D003453:Cryptococcosis / Q000276:immunology*; D003455:Cryptococcus neoformans / Q000276:immunology / Q000302:isolation & purification; D004195:Disease Models, Animal; D005260:Female; D008172:Lung Diseases, Fungal / Q000276:immunology*; D008264:Macrophages / Q000166:cytology / Q000276:immunology*; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D008822:Mice, Transgenic; D011956:Receptors, Cell Surface / Q000172:deficiency / Q000276:immunology*; D018418:Th2 Cells / Q000276:immunology*; D053662:Interleukin-4 Receptor alpha Subunit
chemical_list: D011956:Receptors, Cell Surface; C504002:Il4ra protein, mouse; D053662:Interleukin-4 Receptor alpha Subunit
keywords: cytokine receptor; infection; macrophage; pulmonary cryptococcosis