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

被引:400
作者
Li, Li [1 ,2 ]
Huang, Liping [1 ,2 ]
Vergis, Amy L. [1 ,2 ]
Ye, Hong [1 ,2 ]
Bajwa, Amandeep [1 ,2 ]
Narayan, Vivek [1 ,2 ]
Strieter, Robert M. [1 ,2 ]
Rosin, Diane L. [2 ,3 ]
Okusa, Mark D. [1 ,2 ]
机构
[1] Univ Virginia, Dept Med, Charlottesville, VA USA
[2] Univ Virginia, Ctr Immun Inflammat & Regenerat Med, Charlottesville, VA USA
[3] Univ Virginia, Dept Pharmacol, Charlottesville, VA 22908 USA
关键词
KILLER T-CELLS; DENDRITIC CELLS; BONE-MARROW; INTERLEUKIN-17; FAMILY; INTERFERON-GAMMA; IN-VIVO; INFLAMMATION; ACTIVATION; IL-23; RECEPTORS;
D O I
10.1172/JCI38702
中图分类号
R-3 [医学研究方法]; R3 [基础医学];
学科分类号
1001 ;
摘要
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 1111 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.
引用
收藏
页码:331 / 342
页数:12
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