IL-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 Cryplococcus neoformans-induced bronchopulmonary disease. To study the roles of IL-4 and IL-13 in cerebral cryptococcosis, IL-4 receptor a-deficient (IL-4R alpha(-/-)), IL-4-deficient (IL-4(-/-)), IL-13-deficient (IL-13(-/-)), IL-13 transgenic (IL-13(+/+)), and wild-type mice were infected intranasally. IL-13(+/+) mice displayed a higher fungal brain burden than wild-type mice, whereas the brain burdens of IL-4R alpha(-/-), 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-13(+/+) mice developed significant cerebral lesions. In contrast, only a few IL-4R alpha(-/-), IL-4(-/-), and IL-13(-/-) mice had small lesions in their brains. Furthermore, IL-13(+/+) 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-4R alpha(-/-) 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-4R alpha expression levels as macrophages. These data provide the first evidence of the development of aaMphs in a central nervous system infections disease model, pointing to distinct roles of macrophages versus microglial cells in the central nervous system immune response against C. neoformans. (Am J Pathol 2009, 174:486-496; DOI: 10.2353/ajpath.2009.080598)