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

Abstract

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 Candida albicans 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 Il33−/− mice and in vitro immune cell culture. Tubular epithelial cells mainly secreted IL-33 in response to systemic C. albicans infection. Il33−/− 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 C. albicans infection, which in turn promoted the phagocytosis of neutrophils through secretion of GM-CSF by NK cells. The susceptibility of Il33−/− mice was also associated with increased levels of IL-10, and neutralization of IL-10 resulted in enhanced fungal clearance in Il33−/− mice. However, depletion of IL-10 overrode the effect of IL-33 on fungal clearance. In Il10−/− mouse kidneys, MHC class II+F4/80+ macrophages were massively differentiated after C. albicans 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 C. albicans. Taken together, our results identify IL-33 as critical early regulator controlling a serial downstream signaling events of innate defense to C. albicans infection.