Detrimental impact of the IL-33/ST2 axis in an animal infection model with Cryptococcus neoformans

Cryptococcus neoformans and Cryptococcus gattii are pathogenic fungi that infect the human respiratory system and cause life-threatening pulmonary cryptococcosis. The immunopathology of cryptococcosis is completely different from that of other fungal allergies. In murine cryptococcal infection models, cryptococcal cells are usually injected via nasal or intratracheal routes. After the infection, the alveolar epithelial cells are impaired and release IL-33, an IL-1 family cytokine that functions as an alarmin. This cytokine detrimentally amplifies allergic responses, and also induces a protective immune response against parasitic infection. In the pulmonary cryptococcosis model, type-II alveolar epithelial cells are the major source of IL33, and the alveolar epithelial cells, ILC2, and Th2 cells express the IL-33 receptor (ST2). In IL-33- or ST2deficient mice, allergy-like immune responses are attenuated after the C. neoformans infection. The numbers of ILC2 and Th2 cells and the levels of type 2 cytokines, including IL-4, IL-5, and IL-13, are decreased in the mouse lungs in both models. In association with these changes, total blood IgE, bronchus mucus production, and the number of eosinophils are decreased. Conversely, lung neutrophils and M1type macrophages are increased. These are protective immune subsets suppressing cryptococcal growth. As a result, the lung fungal burden of IL-33- and ST2-deficient mice is decreased post-infection, and both deficient mice show significantly improved mortality. This pathogenesis varies depending on the cryptococcal and murine strains used in the animal experiments. Here, we overview and discuss the itmmunopathology of the IL-33/ST2 axis in a murine lethal cryptococcal infection model. (c) 2023 Japanese Society of Allergology. Published by Elsevier B.V. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

Automated summary

Cryptococcus neoformans and Cryptococcus gattii are pathogenic fungi causing life-threatening pulmonary cryptococcosis. The immunopathology of pulmonary cryptococcosis differs from other fungal allergies, with the IL-33/ST2 axis playing a crucial role post-infection.