Signals of vagal circuits engaging with AKT1 in α7 nAChR(+)CD11b(+) cells lessen E. coli and LPS-induced acute inflammatory injury.
Signals of vagal circuits engaging with AKT1 in α7 nAChR(+)CD11b(+) cells lessen E. coli and LPS-induced acute inflammatory injury.
复制标题
迷走神经回路信号与 α7 nAChR CD11b 细胞中的 AKT1 结合可减轻大肠杆菌和 LPS 诱导的急性炎症损伤
DOI：
10.1038/celldisc.2017.9
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发表时间：
2017
期刊：
影响因子：
33.5
通讯作者：
Su X
中科院分区：
文献类型：
--
作者：
Zhao C;Yang X;Su EM;Huang Y;Li L;Matthay MA;Su X
迷走神经回路-α7 nAChR（α7烟碱乙酰胆碱受体，由Chrna 7编码）信号传导利用脾脏作为中枢来抑制全身炎症反应。迷走神经支配也延伸到远端气道和肺泡。迷走神经切断和α7 nAChR缺乏可使E.大肠杆菌和脂多糖（LPS）诱导的急性肺部炎症反应，然而，其潜在的机制仍然是难以捉摸的。在此，我们假设迷走神经回路通过AKT 1的磷酸化限制α7 nAChR+ CD 11b+细胞（CD 11b由Itgam编码，Itgam是单核细胞和中性粒细胞的表面标志物）的脾释放和肺募集，并且该过程将确定肺损伤的严重程度。利用E. coli和LPS诱导的肺损伤小鼠模型中，迷走神经切断增加了脾细胞的排出和肺内α7 nAChR+ CD 11b+细胞的募集，从而加重了肺的炎症反应。用α7 nAChR激动剂补救迷走神经切断术保留了脾脏中的α7 nAChR+ CD 11b+细胞，抑制了这些细胞向肺的募集，并减弱了肺部炎症反应。通过α7 nAChR的迷走神经信号促进α7 nAChR+ CD 11b+细胞中AKT 1的丝氨酸473磷酸化，并使这些细胞在脾脏中稳定。Akt 1的缺失增强了α7 nAChR+ CD 11b+细胞的脾排出和肺募集，从而引起嗜中性粒细胞浸润的肺炎症和损伤。迷走神经切断术和Chrna 7和Itgam的双缺失减少了脾和支气管肺泡灌洗（BAL）Ly 6 CintGr 1hi中性粒细胞和Ly 6 Chi单核细胞中AKT 1的丝氨酸473磷酸化，它们促进了中性粒细胞和单核细胞向E.大肠杆菌损伤的肺Chrna 7和Itgam的双缺失增加了单核细胞和/或中性粒细胞的肺募集，并恶化了E. coli和LPS诱导的肺损伤。因此，在α7 nAChR+ CD 11b+细胞中，迷走神经回路与AKT 1结合的信号减弱E. coli和LPS诱导的急性肺炎症反应。靶向这一信号通路可以为治疗急性肺损伤提供新的治疗策略。
Vagal circuits-α7 nAChR (α7 nicotinic acetylcholine receptor, coded by Chrna7) signaling utilizes spleen as a hub to dampen systemic inflammatory responses. Vagal innervations also extend to the distal airways and alveoli. Vagotomy and deficiency of α7 nAChR deteriorate E. coli and lipopolysaccharide (LPS)-induced acute lung inflammatory responses; however, the underlying mechanisms remain elusive. Here, we hypothesized that vagal circuits would limit splenic release and lung recruitment of α7 nAChR+CD11b+ cells (CD11b is coded by Itgam, a surface marker of monocytes and neutrophils) via phosphorylation of AKT1 and that this process would define the severity of lung injury. Using both E. coli and LPS-induced lung injury mouse models, we found that vagotomy augmented splenic egress and lung recruitment of α7 nAChR+CD11b+ cells, and consequently worsened lung inflammatory responses. Rescue of vagotomy with an α7 nAChR agonist preserved α7 nAChR+CD11b+ cells in the spleen, suppressed recruitment of these cells to the lung and attenuated lung inflammatory responses. Vagal signals via α7 nAChR promoted serine473 phosphorylation of AKT1 in α7 nAChR+CD11b+ cells and stabilized these cells in the spleen. Deletion of Akt1 enhanced splenic egress and lung recruitment of α7 nAChR+CD11b+ cells, which elicited neutrophil-infiltrated lung inflammation and injury. Vagotomy and double deletion of Chrna7 and Itgam reduced serine473 phosphorylation of AKT1 in the spleen and BAL (bronchoalveolar lavage) Ly6CintGr1hi neutrophils and Ly6Chi monocytes, and they facilitated the recruitment of neutrophils and monocytes to the airspaces of E. coli-injured lungs. Double deletion of Chrna7 and Itgam increased lung recruitment of monocytes and/or neutrophils and deteriorated E. coli and LPS-induced lung injury. Thus, signals of vagal circuits engaging with AKT1 in α7 nAChR+CD11b+ cells attenuate E. coli and LPS-induced acute lung inflammatory responses. Targeting this signaling pathway could provide novel therapeutic strategies for treating acute lung injury.