IL-17 produced by neutrophils regulates IFN-γ–mediated neutrophil migration in mouse kidney ischemia-reperfusion injury
Li Li, … , Diane L. Rosin, Mark D. Okusa
Li Li, … , Diane L. Rosin, Mark D. Okusa
Published December 14, 2009
Citation Information: J Clin Invest. 2010;120(1):331-342. https://doi.org/10.1172/JCI38702.
View: Text | PDF
Research Article Nephrology

IL-17 produced by neutrophils regulates IFN-γ–mediated neutrophil migration in mouse kidney ischemia-reperfusion injury

Abstract

The IL-23/IL-17 and IL-12/IFN-γ cytokine pathways have a role in chronic autoimmunity, which is considered mainly a dysfunction of adaptive immunity. The extent to which they contribute to innate immunity is, however, unknown. We used a mouse model of acute kidney ischemia-reperfusion injury (IRI) to test the hypothesis that early production of IL-23 and IL-12 following IRI activates downstream IL-17 and IFN-γ signaling pathways and promotes kidney inflammation. Deficiency in IL-23, IL-17A, or IL-17 receptor (IL-17R) and mAb neutralization of CXCR2, the p19 subunit of IL-23, or IL-17A attenuated neutrophil infiltration in acute kidney IRI in mice. We further demonstrate that IL-17A produced by GR-1+ neutrophils was critical for kidney IRI in mice. Activation of the IL-12/IFN-γ pathway and NKT cells by administering α-galactosylceramide–primed bone marrow–derived DCs increased IFN-γ production following moderate IRI in WT mice but did not exacerbate injury or enhance IFN-γ production in either Il17a–/– or Il17r–/– mice, which suggested that IL-17 signaling was proximal to IFN-γ signaling. This was confirmed by the finding that IFN-γ administration reversed the protection seen in Il17a–/– mice subjected to IRI, whereas IL-17A failed to reverse protection in Ifng–/– mice. These results demonstrate that the innate immune component of kidney IRI requires dual activation of the IL-12/IFN-γ and IL-23/IL-17 signaling pathways and that neutrophil production of IL-17A is upstream of IL-12/IFN-γ. These mechanisms might contribute to reperfusion injury in other organs.

Authors

Li Li, Liping Huang, Amy L. Vergis, Hong Ye, Amandeep Bajwa, Vivek Narayan, Robert M. Strieter, Diane L. Rosin, Mark D. Okusa

×

Figure 1

The IL-23/IL-17 pathway contributes to kidney IRI.

Options: View larger image (or click on image) Download as PowerPoint
The IL-23/IL-17 pathway contributes to kidney IRI. (A) mRNA levels of p4...
(A) mRNA levels of p40 and p19 were measured by real-time PCR in kidneys after 28 minutes of ischemia and exposure to different times of reperfusion. Values are expressed as relative gene expression (compared with GAPDH) in sham-operated samples and IRI samples following different times of reperfusion. n = 3–5. *P < 0.05 compared with sham. (B) Plasma creatinine was measured as an indication of kidney function in mice exposed to sham operation or IRI (ischemia followed by 24 hours of reperfusion). IgG1, WT mice that received 100 μg IgG1 isotype control 18 hours prior to kidney IRI; anti-p19, WT mice that received anti-p19 mAb treatment 18 hours prior to kidney IRI. n = 4–18; *P < 0.05; **P < 0.01; ***P < 0.001. (C) Representative morphology (by H&E staining) of kidney outer medulla from WT, p40–/–, and p19–/– sham and IRI mice. (D) Plasma creatinine in WT, Il17r–/–, and Il17a–/–, IgG2a, and anti–IL-17A sham and IRI mice after 24 hours of reperfusion. n = 4–9; *P < 0.05; ***P < 0.001. (E) H&E staining of kidney outer medulla from WT, Il17r–/–, and Il17a–/– sham and IRI mice after 24 hours of reperfusion. In C and E, arrowheads indicate necrotic tubules. Scale bars: 100 μm. Values are mean ± SEM.