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.
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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

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Figure 6

Both IL-12/IFN-γ and IL-23/IL-17 pathways are necessary in activated NKT cell–promoted kidney IRI inflammation.

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Both IL-12/IFN-γ and IL-23/IL-17 pathways are necessary in activated NKT...
(A–C) Plasma creatinine levels in mice 24 hours after kidney IRI. (A) Plasma creatinine levels in WT, p35–/–, and Ifng–/– mice or in WT mice after administration of anti–IFN-γ mAb or isotype control IgG1. n = 2–11; ***P < 0.001. (B) Plasma creatinine levels after adoptive transfer of 6 × 105 unprimed DCs or BMDC-αGalCer (DC-αGC) to NKT cell–deficient WT mice (Cd1d–/– and Ja18–/–) or Ifng–/– mice. BMDC-aGalCer was used to specifically activate NKT cells, which promoted moderate kidney IRI (24 minutes of ischemia) in WT mice. n = 4–12; ***P < 0.001 compared with WT BMDC-αGalCer IRI. (C and D) Adoptive transfer of WT BMDC-αGalCer to WT or KO mice prior to sham operation or moderate (24 minutes ischemia) IRI. (C) Plasma creatinine in WT mice or mice with disrupted IL-12/IFN-γ (p40–/–, p35–/–, Ifng–/–) or IL-23/IL-17 pathway (p40–/–, p19–/–, Il17a–/–, Il17r–/–). n = 4–8; **P < 0.01; ***P < 0.001 compared with WT IRI. (D) The number of IFN-γ–producing GR-1+ neutrophils in the kidney was determined by FACS intracellular staining analysis in WT and IL-12/IFN-γ KO and IL-23/IL-17A/IL-17R KO mice. n = 4–6; ***P < 0.001 compared with KO IRI mice. (E) Plasma IFN-γ levels (measured by ELISA) in mice after adoptive transfer of DCs or BMDC-αGalCer. n = 2–7; **P < 0.01, compared with BMDC-αGalCer–treated IRI KO mice. All values are mean ± SEM.