Abrogation Of Il-4 Receptor-Alpha-Dependent Alternatively Activated Macrophages Is Sufficient To Confer Resistance Against Pulmonary Cryptococcosis Despite An Ongoing T(H)2 Response
INTERNATIONAL IMMUNOLOGY(2013)
摘要
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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关键词
cytokine receptor, infection, macrophage, pulmonary cryptococcosis
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