Regular ArticlesIL-4/IL-13-Dependent Alternative Activation of Macrophages but Not Microglial Cells Is Associated with Uncontrolled Cerebral Cryptococcosis

Both interleukin (IL)-4- and IL-13-dependent Th2-mediated immune mechanisms exacerbate murine Cryptococcus neoformans-induced bronchopulmonary disease. To study the roles of IL-4 and IL-13 in cerebral cryptococcosis, IL-4 receptor α-deficient (IL-4Rα−/−), IL-4-deficient (IL-4−/−), IL-13-deficient (IL-13−/−), IL-13 transgenic (IL-13T/+), and wild-type mice were infected intranasally. IL-13T/+ mice displayed a higher fungal brain burden than wild-type mice, whereas the brain burdens of IL-4Rα−/−, IL-4−/−, and IL-13−/− mice were significantly lower as compared with wild-type mice. On infection, 68% of wild-type mice and 88% of IL-13-overexpressing IL-13T/+ mice developed significant cerebral lesions. In contrast, only a few IL-4Rα−/−, IL-4−/−, and IL-13−/− mice had small lesions in their brains. Furthermore, IL-13T/+ mice harbored large pseudocystic lesions in the central nervous system parenchyma, bordered by voluminous foamy alternatively activated macrophages (aaMphs) that contained intracellular cryptococci, without significant microglial activation. In wild-type mice, aaMphs tightly bordered pseudocystic lesions as well, and these mice, in addition, showed microglial cell activation. Interestingly, in resistant IL-4−/−, IL-13−/−, and IL-4Rα−/− mice, no aaMphs were discernible. Microglial cells of all mouse genotypes neither internalized cryptococci nor expressed markers of alternative activation, although they displayed similar IL-4Rα expression levels as macrophages. These data provide the first evidence of the development of aaMphs in a central nervous system infectious disease model, pointing to distinct roles of macrophages versus microglial cells in the central nervous system immune response against C. neoformans.