IL-33 Enhances Host Tolerance to Candida albicans Kidney Infections through Induction of IL-13 Production by CD4+ T Cells

Abstract

Susceptibility to systemic Candida albicans infection is determined by immune resistance, as well as by the ability to control Candida-induced immunopathologies. We showed previously that exogenous IL-33 can increase resistance to peritoneal C. albicans infection by regulating multiple steps of the neutrophil anti-Candida response. In this study, using a mouse model of systemic candidiasis, we observed that IL-33 administration limited fungal burden and inflammation and increased survival. In kidneys, IL-33 seemed to directly act on neutrophils and CD4+ T cells: IL-33 administration enhanced fungal clearance by increasing neutrophil phagocytic activity without which Candida proliferation was uncontrollable. In contrast, IL-33 stimulated CD4+ T cells to produce IL-13, which, in turn, drove the polarization of macrophages toward the M2 type. Furthermore, the absence of IL-13 abolished IL-33–mediated polarization of M2 macrophages and renal functional recovery. In addition, IL-33 and IL-13 acted synergistically to increase M2 macrophage polarization and its phagocytic activity. Overall, this study identifies IL-33 as a cytokine that is able to induce resistance and tolerance and suggests that targeting resistance and tolerance simultaneously with therapeutic IL-33 may benefit patients with systemic candidiasis.

IL-33-Dependent Endothelial Activation Contributes to Apoptosis and Renal Injury in Orientia tsutsugamushi-Infected Mice

“…However, IL-33 also plays deleterious roles during Cryptococcus neoformans -induced lung mycosis and allergic inflammation in the lungs [ 42 , 43 ]. Research concerning the role of IL-33 in kidney infection is relatively limited, and a few reports are focused on cisplatin or Candida albicans -induced renal injury [ 13 , 44 ]. Our data demonstrate that infection with O .…”

“…In the present study, we found that IL-33 deficiency or exogenous rIL-33 did not drastically change type 1 or type 2 cytokine expression during Orientia infection, as reported in a C . albicans -induced renal injury model [ 44 ]. While IL-33 did not reprogram type 1 vs. type 2 responses during Orientia infection, the IL-33/ST2 signaling significantly amplified the magnitude of pro-inflammatory responses ( Fig 3 ), cellular apoptosis, EC stress and activation, and host death (Figs 4 – 7 ).…”

Emerging Roles of IL-33/ST2 Axis in Renal Diseases

“…Tran et al reported that IL-33 administration enhanced fungal clearance by increasing the phagocytosis activity of neutrophils. Moreover, deletion of IL13 abolished IL-33-mediated polarization of M2 macrophages and renal functional recovery [48]. This study indicates that therapeutic IL-33 may benefit patients with systemic candidiasis [42].…”

“…Endothelial cells [47], cardiomyocytes [26], CD4 + T cells [27], macrophages [48], neutrophils, iNKT cells, and ILC2 cells [49,50] were shown to respond to IL-33 activation through their membrane receptor ST2L. The expression of ST2L or IL-33-responsiveness in tubular epithelial cells (including proximal tubular cells, distal tubular cells, collecting duct cells, and pelvic urothelium), mesangial cells or podocytes has not been fully investigated or reported.…”

Distinct myeloid cell subpopulations in controlling systemic candidiasis

“…In addition, they demonstrated that mice were more resistant when they were adoptively transferred with M2 macrophages, as evidenced with lower kidney fungal burdens, renal pro-inflammatory cytokines production (i.e. IL6, TNFα and IL1β) and serum creatinine levels [109]. Hence, a thorough investigation on CD169 + macrophages will certainly facilitate a more detailed understanding of Candida immunity.…”