IL-17 Produced by Neutrophils Regulates IFN-gamma-mediated Neutrophil Migration in Mouse Kidney Ischemia-Reperfusion Injury

J Clin Invest. 2010 Jan;120(1):331-42. doi: 10.1172/JCI38702. Epub 2009 Dec 14.

Abstract

The IL-23/IL-17 and IL-12/IFN-gamma 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-gamma 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-gamma pathway and NKT cells by administering alpha-galactosylceramide-primed bone marrow-derived DCs increased IFN-gamma production following moderate IRI in WT mice but did not exacerbate injury or enhance IFN-gamma production in either Il17a-/- or Il17r-/- mice, which suggested that IL-17 signaling was proximal to IFN-gamma signaling. This was confirmed by the finding that IFN-gamma 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-gamma and IL-23/IL-17 signaling pathways and that neutrophil production of IL-17A is upstream of IL-12/IFN-gamma. These mechanisms might contribute to reperfusion injury in other organs.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Movement
  • Immunity, Innate
  • Inflammation / etiology
  • Interferon-gamma / physiology*
  • Interleukin-12 / physiology
  • Interleukin-17 / physiology*
  • Interleukin-23 / physiology
  • Kidney / blood supply*
  • Killer Cells, Natural / physiology
  • Lymphocyte Activation
  • Mice
  • Mice, Inbred C57BL
  • Neutrophils / physiology*
  • Receptors, Chemokine / physiology
  • Reperfusion Injury / etiology
  • Reperfusion Injury / immunology*
  • Signal Transduction

Substances

  • Gr-1 protein, mouse
  • Interleukin-17
  • Interleukin-23
  • Receptors, Chemokine
  • Interleukin-12
  • Interferon-gamma