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

• Published in: International immunology 2013-08, Vol.25 (8), p.459-470
• Main Authors: Müller, Uwe, Stenzel, Werner, Piehler, Daniel, Grahnert, Andreas, Protschka, Martina, Köhler, Gabriele, Frey, Oliver, Held, Josephin, Richter, Tina, Eschke, Maria, Kamradt, Thomas, Brombacher, Frank, Alber, Gottfried
• Format: Article
• Language: English
• ISSN: 0953-8178; 1460-2377
• DOI: 10.1093/intimm/dxt003

In the murine model of pulmonary infection with Cryptococcus neoformans, IL-4 receptor α (IL-4Rα)-dependent polyfunctional Th2 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 (LysMCreIL-4Rα–/lox mice) and IL-4Rα–/lox littermates. LysMCreIL-4Rα–/lox mice were significantly more resistant to pulmonary cryptococcosis with higher survival rates and lower lung burden than non-deficient heterozygous littermates. Infected LysMCreIL-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 LysMCreIL-4Rα–/lox and IL-4Rα–/lox control mice, but macrophages from LysMCreIL-4Rα–/lox mice showed a higher potential to produce nitric oxide. In contrast to the differences in the macrophage phenotype, pulmonary Th2 responses were similar in infected LysMCreIL-4Rα–/lox and IL-4Rα–/lox mice with each mouse strain harboring polyfunctional Th2 cells. Consistently, type 2 pulmonary allergic inflammation associated with eosinophil recruitment and epithelial mucus production was present in lungs of both LysMCreIL-4Rα–/lox and IL-4Rα–/lox mice. Our results demonstrate that, despite residual IL-4Rα-independent alternative macrophage activation and ongoing Th2-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.