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 Cryptococcus neoformans-induced bronchopulmonary disease. To study the roles of IL-4 and IL-13 in cerebral cryptococcosis, IL-4 receptor alpha-deficient (IL-4Ralpha(-/-)), 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-4Ralpha(-/-), 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-4Ralpha(-/-), 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-4Ralpha(-/-) 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-4Ralpha 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.
Stenzel
Werner
W
Department of Neuropathology, Charité Universitätsmedizin,Berlin, Germany. werner.stenzel@charite.de
Müller
Uwe
U
Köhler
Gabriele
G
Heppner
Frank L
FL
Blessing
Manfred
M
McKenzie
Andrew N J
AN
Brombacher
Frank
F
Alber
Gottfried
G
D000818:Animals; D005260:Female; D005434:Flow Cytometry; D007150:Immunohistochemistry; D018793:Interleukin-13 / Q000276:immunology* / Q000378:metabolism; D015847:Interleukin-4 / Q000276:immunology* / Q000378:metabolism; D008262:Macrophage Activation / Q000276:immunology; D008264:Macrophages / Q000276:immunology* / Q000378:metabolism; D016919:Meningitis, Cryptococcal / Q000276:immunology* / Q000473:pathology; D051379:Mice; D008822:Mice, Transgenic; D017628:Microglia / Q000276:immunology* / Q000378:metabolism; D046529:Microscopy, Electron, Transmission; D020133:Reverse Transcriptase Polymerase Chain Reaction
D018793:Interleukin-13; D015847:Interleukin-4