Published online before print January 15, 2009

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(American Journal of Pathology. 2009;174:486-496.)
© 2009 American Society for Investigative Pathology
DOI: 10.2353/ajpath.2009.080598

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

Werner Stenzel^*, Uwe Müller, Gabriele Köhler, Frank L. Heppner^*, Manfred Blessing, Andrew N.J. McKenzie^¶, Frank Brombacher^|| and Gottfried Alber

From the Department of Neuropathology,^* Charité Universitätsmedizin, Berlin, Germany; the Institute of Immunology, College of Veterinary Medicine, and the Molecular Pathogenesis Group, Center for Biotechnology and Biomedicine, University of Leipzig, Leipzig, Germany; the Gerhard Domagk Institute for Pathology, University of Münster, Münster, Germany; the Medical Research Council Laboratory of Molecular Biology,^¶ Cambridge, United Kingdom; the Institute of Infectious Disease and Molecular Medicine and International Centre for Genetic Engineering and Biotechnology,|| University of Cape Town, Cape Town, South Africa

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 -deficient (IL-4R^–/–), IL-4-deficient (IL-4^–/–), IL-13-deficient (IL-13^–/–), IL-13 transgenic (IL-13^T/+), and wild-type mice were infected intranasally. IL-13^T/+ mice displayed a higher fungal brain burden than wild-type mice, whereas the brain burdens of IL-4R^–/–, 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^T/+ mice developed significant cerebral lesions. In contrast, only a few IL-4R^–/–, IL-4^–/–, and IL-13^–/– mice had small lesions in their brains. Furthermore, IL-13^T/+ 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^–/– 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 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.

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