*Purpose: Invasive candidiasis could be a cause of morbidity and mortality in immunocompromised patients with organ or bone marrow transplantation. In this study, we systematically analyzed the in vivo functions of endogenous IL-33 using Il33^-/- mice and in vitro immune cell culture.

*Methods: WT and IL-33-deficient mice were infected with C. albicans via intravenous injection. Innate immune responses of the kidney were investigated using various immunological techniques.

*Results: 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 co-stimulating 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 which were produced by Ly6G⁺ neutrophils and MHCII⁺F4/80⁺ macrophages and neutralization of IL-10 resulted in enhanced fungal clearance in Il33^-/- mice. However, depletion of IL-10 overrided the effect of IL-33 on fungal clearance. In Il10^-/- mouse kidneys, MHCII⁺F4/80⁺ macrophages were massively differentiated after C. albicans infection and these cells were superior to MHCII^–F4/80⁺ macrophages that were preferentially differentiated in WT mouse kidneys, in killing of extracellular hyphal C. albicans.

*Conclusions: Our results identify IL-33 as critical early regulator controlling a serial downstream signaling events of innate defense to C. albicans infection.

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