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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

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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 8

Model summarizing the role of the IL-12/IFN-γ and IL-23/IL-17 axes of the innate immune response in kidney IRI.

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Model summarizing the role of the IL-12/IFN-γ and IL-23/IL-17 axes of th...
(A) Injury to kidney epithelial cells early (6 hours) following IRI promotes inflammation by increasing pro-inflammatory cytokine/chemokine production, including neutrophil chemoattractant chemokines (CXCL1 and CXCL2). CXCL1 and CXCL2 mediate PMN recruitment and kidney injury through the chemokine receptor CXCR2 (expressed mainly on neutrophils). Autocrine CXCL1/2 production by infiltrating PMNs likely stimulates additional infiltration. (B) Both IL-12/IFN-γ and IL-23/IL-17 pathways are activated in kidney IRI. Kidney resident DCs initiate the immune response following kidney IRI by secreting IL-12 and IL-23. DCs activate NKT cells by CD1d-mediated glycolipid presentation and CD40/CD40L costimulation. IL-12 mediates NKT cell activation and IFN-γ production, which further stimulates neutrophil IFN-γ production and infiltration of PMNs and other immune cells (CD4+ and NKT cells and macrophages; not shown) that contribute to kidney injury. IL-23 is also involved in NKT cell activation (our unpublished observations). IL-23 (with TGF-β and IL-6; not shown) is known to induce Th17 cell differentiation, but neutrophils, not Th17 cells, are the predominant source of IL-17A in the innate immune response in kidney IRI. IL-23 and its downstream cytokine IL-17A induce pro-inflammatory cytokine (IL-6, IL-1β, TNF-α) and chemokine (CXCL1/2) (not shown) production to promote kidney inflammation. (C) The IL-23/IL-17 axis is proximal to and necessary for IL-12/IFN-γ–mediated tissue injury through NKT cell activation. IL-17A produced from PMNs regulates NKT cell activation, IFN-γ production, PMN infiltration and tissue injury in kidney IRI. Therefore, in addition to IL-12/IFN-γ, IL-23 and IL-17 signal pathways also participate in the innate immune response to IRI by stimulating activated NKT cell–mediated kidney inflammation and PMN infiltration.

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ISSN: 0021-9738 (print), 1558-8238 (online)

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