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
View: Text | PDF
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

×

Figure 2

RTEC-specific expression of IL-17RA is required for antifungal immunity in the kidney.

Options: View larger image (or click on image) Download as PowerPoint
RTEC-specific expression of IL-17RA is required for antifungal immunity ...
(A) BM cells from Il17ra−/− (CD45.2+) and WT (CD45.1+) mice were adoptively transferred into irradiated (9 Gy) Il17ra−/− or WT recipients (n = 14). Six weeks later, mice were systemically infected with C. albicans, and survival was evaluated over 14 days. Don, donor; rec, recipients. (B) Total kidney cells from WT, Il17ra–/–, control, and Il17raΔRTEC mice (n = 3) were evaluated for IL-17RA expression on RTEC (live CD45–CD133+). The number in the contour plot reflects percentage of cells. Histogram is representative of 1 of 3 independent experiments. (C) Control, Il17raΔRTEC, and Il17ra–/– mice were systemically infected with C. albicans (CAF2-1 strain; 1 × 105 CFU) (n = 15–16) or left uninfected (n = 3–5). Mice were evaluated for survival over 14 days. (D) Control, Il17raΔRTEC, and Il17ra–/– mice were systemically infected with C. albicans (HUN96 strain; 5 × 105 CFU) (n = 8–11) or left uninfected (n = 2). Mice were evaluated for survival over 14 days. (E) Il17rafl/flNpsh2Cre- (control) and Il17rafl/flNpsh2Cre+ (Il17raΔPOD) mice were either subjected to infection (n = 8–10) or left uninfected (n = 3) and were evaluated for survival over 14 days. Data are pooled from 3 independent experiments for A, C, and E and 2 independent experiments for D. The comparison of survival curves were performed by Log-rank (Mantel-Cox) test. *P < 0.05; **P < 0.01; ***P < 0.001; ****P < 0.0001.