Journal
INTERNATIONAL IMMUNOLOGY
Volume 25, Issue 8, Pages 459-470Publisher
OXFORD UNIV PRESS
DOI: 10.1093/intimm/dxt003
Keywords
cytokine receptor; infection; macrophage; pulmonary cryptococcosis
Categories
Funding
- Deutsche Forschungsgemeinschaft (German Research Foundation) [AL 371/5-4]
- South African Research Chair Initiative
- South African Medical Research Council
- Else Kroner-Fresenius-Stiftung
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In the murine model of pulmonary infection with Cryptococcus neoformans, IL-4 receptor (IL-4R)-dependent polyfunctional T(h)2 cells induce disease progression associated with alternative activation of lung macrophages. To characterize the effector role of IL-4R-dependent alternatively activated macrophages (aaMph), we intra-nasally infected mice with genetically ablated IL-4R expression on macrophages (LysM(Cre)IL-4R(/lox) mice) and IL-4R(/lox) littermates. LysM(Cre)IL-4R(/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-4R(/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-4R(/lox) and IL-4R(/lox) control mice, but macrophages from LysM(Cre)IL-4R(/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-4R(/lox) and IL-4R(/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-4R(/lox) and IL-4R(/lox) mice. Our results demonstrate that, despite residual IL-4R-independent alternative macrophage activation and ongoing T(h)2-dependent allergic inflammation, abrogation of IL-4R-dependent aaMph is sufficient to confer resistance in pulmonary cryptococcosis. This is even evident on a relatively resistant heterozygous IL-4R(/) background indicating a key contribution of macrophage IL-4R expression to susceptibility in allergic bronchopulmonary mycosis.
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