Abrogation of IL-4 receptor-α-dependent alternatively activated macrophages is sufficient to confer resistance against pulmonary cryptococcosis despite an ongoing Th2 response | Zendy

Uwe Müller | Zendy; Werner Stenzel | Zendy; Daniel Piehler | Zendy; Andreas Grahnert | Zendy; Martina Protschka | Zendy; Gabriele Köhler | Zendy; Oliver Frey | Zendy; Josephin Held | Zendy; Tina Richter | Zendy; Maria Eschke | Zendy; Thomas Kamradt | Zendy; Frank Brombacher | Zendy; Gottfried Alber | Zendy

Open Access

Abrogation of IL-4 receptor-α-dependent alternatively activated macrophages is sufficient to confer resistance against pulmonary cryptococcosis despite an ongoing Th2 response

Author(s) -

Uwe Müller,

Werner Stenzel,

Daniel Piehler,

Andreas Grahnert,

Martina Protschka,

Gabriele Köhler,

Oliver Frey,

Josephin Held,

Tina Richter,

Maria Eschke,

Thomas Kamradt,

Frank Brombacher,

Gottfried Alber

Publication year - 2013

Publication title -

international immunology

Language(s) - English

Resource type - Journals

SCImago Journal Rank - 1.86

H-Index - 134

eISSN - 1460-2377

pISSN - 0953-8178

DOI - 10.1093/intimm/dxt003

Subject(s) - immunology , cryptococcus neoformans , interleukin 4 , inflammation , macrophage , biology , cryptococcosis , cytokine , chemistry , microbiology and biotechnology , in vitro , biochemistry

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.

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