IL-13 induces disease-promoting type 2 cytokines, alternatively activated macrophages and allergic inflammation during pulmonary infection of mice with Cryptococcus neoformans.
In the murine model of Cryptococcus neoformans infection Th1 (IL-12/IFN-gamma) and Th17 (IL-23/IL-17) responses are associated with protection, whereas an IL-4-dependent Th2 response exacerbates disease. To investigate the role of the Th2 cytokine IL-13 during pulmonary infection with C. neoformans, IL-13-overexpressing transgenic (IL-13Tg(+)), IL-13-deficient (IL-13(-/-)), and wild-type (WT) mice were infected intranasally. Susceptibility to C. neoformans infection was found when IL-13 was induced in WT mice or overproduced in IL-13Tg(+) mice. Infected IL-13Tg(+) mice had a reduced survival time and higher pulmonary fungal load as compared with WT mice. In contrast, infected IL-13(-/-) mice were resistant and 89% of these mice survived the entire period of the experiment. Ag-specific production of IL-13 by susceptible WT and IL-13Tg(+) mice was associated with a significant type 2 cytokine shift but only minor changes in IFN-gamma production. Consistent with enhanced type 2 cytokine production, high levels of serum IgE and low ratios of serum IgG2a/IgG1 were detected in susceptible WT and IL-13Tg(+) mice. Interestingly, expression of IL-13 by susceptible WT and IL-13Tg(+) mice was associated with reduced IL-17 production. IL-13 was found to induce formation of alternatively activated macrophages expressing arginase-1, macrophage mannose receptor (CD206), and YM1. In addition, IL-13 production led to lung eosinophilia, goblet cell metaplasia and elevated mucus production, and enhanced airway hyperreactivity. This indicates that IL-13 contributes to fatal allergic inflammation during C. neoformans infection.
Müller
Uwe
U
Institute of Immunology, College of Veterinary Medicine, University of Leipzig, Leipzig, Germany.
Stenzel
Werner
W
Köhler
Gabriele
G
Werner
Christoph
C
Polte
Tobias
T
Hansen
Gesine
G
Schütze
Nicole
N
Straubinger
Reinhard K
RK
Blessing
Manfred
M
McKenzie
Andrew N J
AN
Brombacher
Frank
F
Alber
Gottfried
G
D000818:Animals; D000908:Antibodies, Fungal / Q000096:biosynthesis / Q000145:classification; D003453:Cryptococcosis / Q000276:immunology*; D003455:Cryptococcus neoformans / Q000276:immunology; D016207:Cytokines / Q000096:biosynthesis*; D005260:Female; D007132:Immunoglobulin Isotypes / Q000096:biosynthesis; D007249:Inflammation / Q000276:immunology / Q000469:parasitology / Q000473:pathology; D018793:Interleukin-13 / Q000096:biosynthesis / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D008172:Lung Diseases, Fungal / Q000276:immunology* / Q000401:mortality / Q000469:parasitology / Q000473:pathology*; D008262:Macrophage Activation; D016676:Macrophages, Alveolar / Q000276:immunology* / Q000378:metabolism / Q000469:parasitology; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D008822:Mice, Transgenic; D012130:Respiratory Hypersensitivity / Q000276:immunology* / Q000469:parasitology / Q000473:pathology*
D000908:Antibodies, Fungal; D016207:Cytokines; D007132:Immunoglobulin Isotypes; D018793:Interleukin-13