AbstractIn 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.