1. IL-17 produced by neutrophils regulates IFN-gamma-mediated neutrophil migration in mouse kidney ischemia-reperfusion injury.
- Author
-
Li Li, Liping Huang, Vergis, Amy L., Hong Ye, Bajwa, Amandeep, Narayan, Vivek, Strieter, Robert M., Rosin, Diane L., Okusa, Mark D., Li, Li, Huang, Liping, and Ye, Hong
- Subjects
- *
KIDNEY diseases in animals , *NEUTROPHILS , *ISCHEMIA , *AUTOIMMUNITY , *CYTOKINES , *ANIMAL diseases , *ANIMAL disease models , *PREVENTION , *KILLER cells , *CELL receptors , *ANIMAL experimentation , *CELL motility , *CELLULAR signal transduction , *COMPARATIVE studies , *IMMUNITY , *IMMUNOLOGY technique , *INFLAMMATION , *INTERFERONS , *INTERLEUKINS , *KIDNEYS , *RESEARCH methodology , *MEDICAL cooperation , *MICE , *REPERFUSION injury , *RESEARCH , *RESEARCH funding , *EVALUATION research , *PHYSIOLOGY , *CELL physiology - 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. [ABSTRACT FROM AUTHOR]
- Published
- 2010
- Full Text
- View/download PDF