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

作者：Mueller Uwe; Stenzel Werner; Piehler Daniel; Grahnert Andreas; Protschka Martina; Koehler Gabriele; Frey Oliver; Held Josephin; Richter Tina; Eschke Maria; Kamradt Thomas; Brombacher Frank; Alber Gottfried^*

来源：International Immunology, 2013, 25(8): 459-470.

DOI：10.1093/intimm/dxt003

• cytokine receptor
• infection
• macrophage
• pulmonary cryptococcosis

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.

• 出版日期2013-8