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

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

Research output: Contribution to journalArticle

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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.

Original languageEnglish (US)
Pages (from-to)331-342
Number of pages12
JournalJournal of Clinical Investigation
Volume120
Issue number1
DOIs
StatePublished - Jan 4 2010

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Interleukin-17
Reperfusion Injury
Neutrophils
Kidney
Interleukin-23
Interleukin-12
Interleukin-23 Subunit p19
Interleukin-17 Receptors
Galactosylceramides
Natural Killer T-Cells
Neutrophil Infiltration
Adaptive Immunity
Autoimmunity
Innate Immunity
Bone Marrow
Cytokines
Inflammation
Wounds and Injuries

All Science Journal Classification (ASJC) codes

  • Medicine(all)

Cite this

IL-17 produced by neutrophils regulates IFN-γ-mediated neutrophil migration in mouse kidney ischemia-reperfusion injury. / Li, Li; Huang, Liping; Vergis, Amy L.; Ye, Hong; Bajwa, Amandeep; Narayan, Vivek; Strieter, Robert M.; Rosin, Diane L.; Okusa, Mark D.

In: Journal of Clinical Investigation, Vol. 120, No. 1, 04.01.2010, p. 331-342.

Research output: Contribution to journalArticle

Li, Li ; Huang, Liping ; Vergis, Amy L. ; Ye, Hong ; Bajwa, Amandeep ; Narayan, Vivek ; Strieter, Robert M. ; Rosin, Diane L. ; Okusa, Mark D. / IL-17 produced by neutrophils regulates IFN-γ-mediated neutrophil migration in mouse kidney ischemia-reperfusion injury. In: Journal of Clinical Investigation. 2010 ; Vol. 120, No. 1. pp. 331-342.
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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.",
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AU - Bajwa, Amandeep

AU - Narayan, Vivek

AU - Strieter, Robert M.

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AU - Okusa, Mark D.

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