IL-4 receptor-alpha-dependent control of Cryptococcus neoformans in the early phase of pulmonary infection

• Published in: PloS one 2014-01, Vol.9 (1), p.e87341-e87341
• Main Authors: Grahnert, Andreas, Richter, Tina, Piehler, Daniel, Eschke, Maria, Schulze, Bianca, Müller, Uwe, Protschka, Martina, Köhler, Gabriele, Sabat, Robert, Brombacher, Frank, Alber, Gottfried
• Format: Article
• Language: English
• Subjects: Airway management; Animals; Antibodies, Monoclonal - immunology; Asthma; Biology; Biotechnology; CCL20 protein; Chemokines; Cryptococcosis; Cryptococcosis - immunology; Cryptococcus neoformans; Cryptococcus neoformans - immunology; Cytokines; Dendritic cells; Dendritic Cells - immunology; Diseases; DNA Primers - genetics; Enzyme-Linked Immunosorbent Assay; Experiments; Female; Flow Cytometry; Fungal infections; Fungi; Health aspects; Immune response; Immunology; Infection control; Interferon; Interferon-gamma - immunology; Interleukin; Interleukin 10; Interleukin 12; Interleukin 4; Interleukin-10 - immunology; Interleukin-12 - immunology; Interleukin-4 Receptor alpha Subunit - genetics; Interleukin-4 Receptor alpha Subunit - immunology; Interleukins; Laboratory animals; Lung diseases; Lungs; Macrophages; Macrophages - immunology; Medical research; Medicine; Meningoencephalitis; Mice; Mice, Inbred C57BL; Mice, Knockout; Monocyte chemoattractant protein 1; Nitric oxide; Opportunist infection; Pathogenesis; Pathogens; Pneumonia - immunology; Pneumonia - microbiology; Recruitment; Rodents; Signal Transduction - immunology; Signaling; Stability; Tropical diseases; Veterinary colleges; Veterinary medicine; γ-Interferon
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0087341

Cryptococcus neoformans is an opportunistic fungal pathogen that causes lung inflammation and meningoencephalitis in immunocompromised people. Previously we showed that mice succumb to intranasal infection by induction of pulmonary interleukin (IL)-4Rα-dependent type 2 immune responses, whereas IL-12-dependent type 1 responses confer resistance. In the experiments presented here, IL-4Rα⁻/⁻ mice unexpectedly show decreased fungal control early upon infection with C. neoformans, whereas wild-type mice are able to control fungal growth accompanied by enhanced macrophage and dendritic cell recruitment to the site of infection. Lower pulmonary recruitment of macrophages and dendritic cells in IL-4Rα⁻/⁻ mice is associated with reduced pulmonary expression of CCL2 and CCL20 chemokines. Moreover, IFN-γ and nitric oxide production are diminished in IL-4Rα⁻/⁻ mice compared to wild-type mice. To directly study the potential mechanism(s) responsible for reduced production of IFN-γ, conventional dendritic cells were stimulated with C. neoformans in the presence of IL-4 which results in increased IL-12 production and reduced IL-10 production. Together, a beneficial role of early IL-4Rα signaling is demonstrated in pulmonary cryptococcosis, which contrasts with the well-known IL-4Rα-mediated detrimental effects in the late phase.