[HTML][HTML] Unexpected kidney-restricted role for IL-17 receptor signaling in defense against systemic Candida albicans infection

K Ramani, CV Jawale, AH Verma, BM Coleman… - JCI insight, 2018 - ncbi.nlm.nih.gov
JCI insight, 2018ncbi.nlm.nih.gov
Kidney injury is a frequent outcome in patients with disseminated Candida albicans fungal
infections. IL-17 receptor (IL-17R) signaling is critical for renal protection against
disseminated candidiasis, but the identity and function of IL-17–responsive cells in
mediating renal defense remains an active area of debate. Using BM chimeras, we found
that IL-17R signaling is required only in nonhematopoietic cells for immunity to systemic C.
albicans infection. Since renal tubular epithelial cells (RTEC) are highly responsive to IL-17 …
Abstract
Kidney injury is a frequent outcome in patients with disseminated Candida albicans fungal infections. IL-17 receptor (IL-17R) signaling is critical for renal protection against disseminated candidiasis, but the identity and function of IL-17–responsive cells in mediating renal defense remains an active area of debate. Using BM chimeras, we found that IL-17R signaling is required only in nonhematopoietic cells for immunity to systemic C. albicans infection. Since renal tubular epithelial cells (RTEC) are highly responsive to IL-17 in vitro, we hypothesized that RTEC might be the dominant target of IL-17 activity in the infected kidney. We generated mice with a conditional deletion of IL-17 receptor A (Il17ra) in RTEC (Il17ra ΔRTEC). Strikingly, Il17ra ΔRTEC mice showed enhanced kidney damage and early mortality following systemic infection, very similar to Il17ra–/–animals. Increased susceptibility to candidiasis in Il17ra ΔRTEC mice was associated with diminished activation of the renal protective Kallikrein-kinin system (KKS), resulting in reduced apoptosis of kidney-resident cells during hyphal invasion. Moreover, protection was restored by treatment with bradykinin, the major end-product of KKS activation, which was mediated dominantly via bradykinin receptor b1. These data show that IL-17R signaling in RTEC is necessary and likely sufficient for IL-17–mediated renal defense against fatal systemic C. albicans infection.
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