Unexpected kidney-restricted role for IL-17 receptor signaling in defense against systemic Candida albicans infection
Kritika Ramani, Chetan V. Jawale, Akash H. Verma, Bianca M. Coleman, Jay K. Kolls, Partha S. Biswas
Kritika Ramani, Chetan V. Jawale, Akash H. Verma, Bianca M. Coleman, Jay K. Kolls, Partha S. Biswas
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Research Article Immunology Infectious disease

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

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 (Il17raΔRTEC). Strikingly, Il17raΔRTEC mice showed enhanced kidney damage and early mortality following systemic infection, very similar to Il17ra–/– animals. Increased susceptibility to candidiasis in Il17raΔRTEC 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.

Authors

Kritika Ramani, Chetan V. Jawale, Akash H. Verma, Bianca M. Coleman, Jay K. Kolls, Partha S. Biswas

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Figure 7

Diminished activation of KKS in the C.

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Diminished activation of KKS in the C. albicans–infected kidney ofIl17r...
albicans–infected kidney ofIl17raΔRTECmice. Control and Il17raΔRTEC mice (n = 8–9) were subjected to systemic C. albicans infection. (A) At day 2 p.i., renal transcript expression of Klk1 and Klk1b26 was measured by qPCR. Each dot represents an individual mouse, and the data are represented as mean ± SD. Data were pooled from 2 independent experiments and analyzed by 2-tailed Student’s t test. (B) Serial kidney sections (n = 6) were stained for Klk1. Original magnification, 100×; scale bars: 400 µm. Representative photomicrographs from 2 independent experiments. (C) Il17raΔRTEC mice (n = 12–15) were treated ± bradykinin (300 nmol/kg/day) starting day –1 (relative to infection) and then daily over 14 days. Control mice were left untreated. Both Il17raΔRTEC and control mice were infected systemically with C. albicans. Sham mice were treated ± bradykinin (n = 3–5). Survival was assessed over 14 days. Data are pooled from 4 independent experiments and analyzed by Log-rank (Mantel Cox) test. (D) WT mice (n = 3–8) were subjected to systemic C. albicans infection. At day 2 p.i., renal transcript expression of Bdkrb1 and Bdkrb2 was quantified by qPCR. Each dot represents individual mouse, and data are represented as mean ± SD. Data are pooled from 2 independent experiments and analyzed by 2-tailed Student’s t test (E) WT mice (n = 10–11) were treated with either Bdkrb1 (R-715; 1 mg/kg/day) or Bdkrb2 (HOE-140; 1 mg/kg/day) antagonists or PBS starting day –1 day relative to infection and then daily over 14 days. Sham mice were treated with the antagonists only (n = 3). Mice were evaluated for survival over 14 days. The data are pooled from 2 independent experiments and analyzed by Log-rank (Mantel Cox) test. *P < 0.05; **P < 0.01; ***P < 0.001; ****P < 0.0001.