IFN-γ induction by neutrophil-derived IL-17A homodimer augments pulmonary antibacterial defense.
IFN-γ induction by neutrophil-derived IL-17A homodimer augments pulmonary antibacterial defense.
复制标题
中性粒细胞衍生的IL-17A同二聚体诱导IFN-γ诱导肺抗菌防御。
DOI：
10.1038/mi.2015.95
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发表时间：
2016-05
影响因子：
8
通讯作者：
Jeyaseelan S
中科院分区：
文献类型：
--
作者：
Cai S;Batra S;Langohr I;Iwakura Y;Jeyaseelan S
IL-17 A在宿主防御嗜肺军团菌中的作用仍然是难以捉摸的。为了解决这个问题，我们在C57 Bl/6（非许可）背景下使用了Il 17 a −/−、Il 17 f −/−和Il 17 a/Il 17 f −/−小鼠，在A/J（许可）背景下使用了IL-17中和抗体。在Il 17 a −/−小鼠中检测到肺和血液中较高的细菌（嗜肺军团菌）计数，沿着中性粒细胞募集减少，但在Il 17 f −/−小鼠中未检测到。我们发现中性粒细胞在L.已知造血细胞来源的IL-17 A对于细菌清除是重要的。因此，WT中性粒细胞或重组IL-17 A的腹膜内（i.t）给药恢复了Il 17 a −/−小鼠的细菌清除和中性粒细胞募集。此外，嗜中性粒细胞耗竭的Rag 2 −/−和Rag 2/Il-2 r γ−/−小鼠表现出肺中细菌负荷增加、中性粒细胞流入减少和IL-17 A产生减少。IL-17 a −/−小鼠中重组IFN-γ给药增强了细菌清除，而IL-17 A给药在Ifnγ−/−小鼠中没有增强细菌清除。IFN-γ由T细胞产生，而不是由嗜中性粒细胞或巨噬细胞产生，表明嗜中性粒细胞衍生的IL-17 A以旁分泌方式诱导IFN-γ。用L.嗜肺菌表现出产生IL-17 A的细胞数量增加。这些发现显示了嗜中性粒细胞衍生的IL-17 A通过以旁分泌方式诱导IFN-γ在抗菌防御中的新功能。
The role of IL-17A in host defense against Legionella pneumophila remains elusive. To address this issue, we used Il17a−/−, Il17f−/−, and Il17a/Il17f−/− mice on a C57Bl/6 (non-permissive) background and IL-17 neutralizing Abs in mice on an A/J (permissive) background. Higher bacterial (L.pneumophila) counts in the lung and blood along with reduced neutrophil recruitment were detected in Il17a−/−, but not Il17f−/−, mice. We found that neutrophils produce IL-17A homodimer (IL-17A) during L. pneumophila infection, and hematopoietic cell-derived IL-17A is known to be important for bacterial clearance. Thus, intratracheal (i.t) administration of WT neutrophils or recombinant IL-17A restored bacterial clearance and neutrophil recruitment in Il17a−/− mice. Furthermore, neutrophil-depleted Rag2−/− and Rag2/Il-2rγ−/− mice exhibited increased bacterial burden, reduced neutrophil influx and IL-17A production in the lung. Recombinant IFN-γ administration in Il17a−/− mice augmented bacterial elimination whereas IL-17A administration in Ifnγ−/− mice did not augment bacterial clearance. IFN-γ is produced by T cells, but not neutrophils or macrophages, suggesting that neutrophil-derived IL-17A induces IFN-γ in a paracrine fashion. Human pneumonic lungs and human neutrophils challenged with L. pneumophila exhibited increased numbers of IL-17A producing cells. These findings display a novel function of neutrophil-derived IL-17A in antibacterial defense via the induction of IFN-γ in a paracrine manner.