IL-33 Coordinates Innate Defense to Systemic Candida albicans Infection by Regulating IL-23 and IL-10 in an Opposite Way

Invasive candidiasis has high mortality rates in immunocompromised patients, causing serious health problems. In mouse models, innate immunity protects the host by rapidly mobilizing a variety of resistance and tolerance mechanisms to systemic infection. We have previously demonstrated that exogenou...

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Bibliographic Details
Published in:	The Journal of immunology (1950) Vol. 208; no. 3; pp. 660 - 671
Main Authors:	Nguyen, Nu Z N, Tran, Vuvi G, Baek, Jiyeon, Kim, Younghee, Youn, Eun H, Na, Seung W, Park, Sang J, Seo, Su-Kil, Kwon, Byungsuk
Format:	Journal Article
Language:	English
Published:	United States 01-02-2022
Subjects:	Animals Candida albicans - immunology Candidiasis - immunology Candidiasis - microbiology Dendritic Cells - immunology Disease Models, Animal Granulocyte-Macrophage Colony-Stimulating Factor - metabolism Histocompatibility Antigens Class II - immunology Immunity, Innate - immunology Immunocompromised Host - immunology Interleukin-10 - genetics Interleukin-10 - metabolism Interleukin-23 Subunit p19 - metabolism Interleukin-33 - genetics Interleukin-33 - immunology Killer Cells, Natural - immunology Macrophages - immunology Mice Mice, Inbred C57BL Mice, Knockout Neutrophils - immunology Phagocytosis - immunology Signal Transduction - immunology
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Summary:	Invasive candidiasis has high mortality rates in immunocompromised patients, causing serious health problems. In mouse models, innate immunity protects the host by rapidly mobilizing a variety of resistance and tolerance mechanisms to systemic infection. We have previously demonstrated that exogenous IL-33 regulates multiple steps of innate immunity involving resistance and tolerance processes. In this study, we systematically analyzed the in vivo functions of endogenous IL-33 using mice and in vitro immune cell culture. Tubular epithelial cells mainly secreted IL-33 in response to systemic infection. mice showed increased mortality and morbidity, which were due to impaired fungal clearance. IL-33 initiated an innate defense mechanism by costimulating dendritic cells to produce IL-23 after systemic infection, which in turn promoted the phagocytosis of neutrophils through secretion of GM-CSF by NK cells. The susceptibility of mice was also associated with increased levels of IL-10, and neutralization of IL-10 resulted in enhanced fungal clearance in mice. However, depletion of IL-10 overrode the effect of IL-33 on fungal clearance. In mouse kidneys, MHC class II F4/80 macrophages were massively differentiated after infection, and these cells were superior to MHC class II F4/80 macrophages that were preferentially differentiated in wild-type mouse kidneys in killing of extracellular hyphal Taken together, our results identify IL-33 as critical early regulator controlling a serial downstream signaling events of innate defense to infection.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23
ISSN:	0022-1767 1550-6606
DOI:	10.4049/jimmunol.2100495