title: IL-17 produced by neutrophils regulates IFN-gamma-mediated neutrophil migration in mouse kidney ischemia-reperfusion injury.
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.
authors.affiliation: Department of Medicine, Center for Immunity, Inflammation, and Regenerative Medicine, University of Virginia, Charlottesville, Virginia 22908, USA. ll3m@virginia.edu
authors.forename: Li
authors.initials: L
authors.lastname: Li
authors.forename: Liping
authors.initials: L
authors.lastname: Huang
authors.forename: Amy L
authors.initials: AL
authors.lastname: Vergis
authors.forename: Hong
authors.initials: H
authors.lastname: Ye
authors.forename: Amandeep
authors.initials: A
authors.lastname: Bajwa
authors.forename: Vivek
authors.initials: V
authors.lastname: Narayan
authors.forename: Robert M
authors.initials: RM
authors.lastname: Strieter
authors.forename: Diane L
authors.initials: DL
authors.lastname: Rosin
authors.forename: Mark D
authors.initials: MD
authors.lastname: Okusa
mesh_terms: D000818:Animals; D002465:Cell Movement; D007113:Immunity, Innate; D007249:Inflammation / Q000209:etiology; D007371:Interferon-gamma / Q000502:physiology*; D018664:Interleukin-12 / Q000502:physiology; D020381:Interleukin-17 / Q000502:physiology*; D053759:Interleukin-23 / Q000502:physiology; D007668:Kidney / Q000098:blood supply*; D007694:Killer Cells, Natural / Q000502:physiology; D008213:Lymphocyte Activation; D051379:Mice; D008810:Mice, Inbred C57BL; D009504:Neutrophils / Q000502:physiology*; D019707:Receptors, Chemokine / Q000502:physiology; D015427:Reperfusion Injury / Q000209:etiology / Q000276:immunology*; D015398:Signal Transduction
chemical_list: C503133:Gr-1 protein, mouse; D020381:Interleukin-17; D053759:Interleukin-23; D019707:Receptors, Chemokine; D018664:Interleukin-12; D007371:Interferon-gamma