The Kallikrein-Kinin System: A Novel Mediator of IL-17-Driven Anti-Candida Immunity in the Kidney

Abstract

The incidence of life-threatening disseminated Candida albicans infections is increasing in hospitalized patients, with fatalities as high as 60%. Death from disseminated candidiasis in a significant percentage of cases is due to fungal invasion of the kidney, leading to renal failure. Treatment of candidiasis is hampered by drug toxicity, the emergence of antifungal drug resistance and lack of vaccines against fungal pathogens. IL-17 is a key mediator of defense against candidiasis. The underlying mechanisms of IL-17-mediated renal immunity have so far been assumed to occur solely through the regulation of antimicrobial mechanisms, particularly activation of neutrophils. Here, we identify an unexpected role for IL-17 in inducing the Kallikrein (Klk)-Kinin System (KKS) in C. albicans-infected kidney, and we show that the KKS provides significant renal protection in candidiasis. Microarray data indicated that Klk1 was upregulated in infected kidney in an IL-17-dependent manner. Overexpression of Klk1 or treatment with bradykinin rescued IL-17RA-/- mice from candidiasis. Therapeutic manipulation of IL-17-KKS pathways restored renal function and prolonged survival by preventing apoptosis of renal cells following C. albicans infection. Furthermore, combining a minimally effective dose of fluconazole with bradykinin markedly improved survival compared to either drug alone. These results indicate that IL-17 not only limits fungal growth in the kidney, but also prevents renal tissue damage and preserves kidney function during disseminated candidiasis through the KKS. Since drugs targeting the KKS are approved clinically, these findings offer potential avenues for the treatment of this fatal nosocomial infection.

Loss of Twist1 in the Mesenchymal Compartment Promotes Increased Fibrosis in Experimental Lung Injury by Enhanced Expression of CXCL12

“…Mouse bone marrow cells were obtained as previously described (23). Cells were then stained with the following: Ly6G-FITC (BD Pharmingen; clone IA8), CD68-PE (Bio Legend; clone FA-11), CD3-APC (BD Pharmingen; clone 145–2011), B220-PeCy7 (BD Pharmingen; clone RA3–6B2), CD4-V450 (BioLegend; clone RM4–5), CD8-PerCP (BD Pharmingen; clone 53-6.7) and Rat Anti-Mouse CD184/CXCR4 (BD Pharmingen; clone 2B11.…”

IL-17 Signaling: The Yin and the Yang

“…In NK cells, IL-17 was reported to induce expression of GM-CSF ( Csf2 ), one of the few documented examples of IL-17-dependent signaling in hematopoietic cells [55]. A recent report showed that IL-17 drives kallikrein 1 ( Klk1 ) expression in renal epithelial cells to confer protection against disseminated candidiasis [56]. IL-17-induced induced receptor activator of NF-κB ligand (RANKL, also known as TNFSF11 or osteoprotegerin ligand, OPGL) expression in osteoblasts promotes differentiation and activation, perhaps accounting for some of the bone-destructive effects of IL-17 observed in models of arthritis or periodontal disease [57, 58], and IL-17 regulates expression of histatins in the salivary compartment that control infection with C. albicans [59].…”

IL-23 supports host defense against systemic Candida albicans infection by ensuring myeloid cell survival

“…IL-23 is well known as a key regulator of IL-17 immunity and the IL-23-IL-17 immune axis plays a pivotal role in host defense against C. albicans at mucosal surfaces [42][43][44]. IL-17 receptor-deficient mice are also highly susceptible to systemic candidiasis [13][14][15]. To assess whether the IL-17 pathway was involved in IL-23-dependent inhibition of myeloid cell apoptosis during systemic candidiasis, we infected Il17ra -/mice and analyzed the viability of myeloid cells 48h post infection (S8A Fig). In sharp contrast to the situation in IL-23-deficient mice, IL-17RA deficiency did not affect the viability of kidney myeloid cells, with the exception of the Ly6C lo myeloid subset, which exhibited a shift in the proportion of the 7-AAD-and Annexin V-stained populations.…”

“…IL-23 expression is strongly induced in response to C. albicans via the C-type lectin pathway [9,10] and is best known for regulating IL-17 production by T cells and innate lymphoid cells [11], which is of particular relevance for antifungal immunity at epithelial barriers [12]. IL-17 also contributes to protection from disseminated candidiasis [13][14][15]. Importantly, a growing body of work suggests that IL-23 possesses functions that exceed regulation of IL-17 immunity.…”