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首页> 外文期刊>Cell discovery. >Signals of vagal circuits engaging with AKT1 in α7 nAChR+CD11b+ cells lessen E. coli and LPS-induced acute inflammatory injury
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Signals of vagal circuits engaging with AKT1 in α7 nAChR+CD11b+ cells lessen E. coli and LPS-induced acute inflammatory injury

机译：与α7nAChR + CD11b + 细胞中的AKT1结合的迷走神经回路的信号会减少 E。和脂多糖诱导的急性炎症损伤

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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.
机译：迷走神经回路-α7nAChR（α7烟碱乙酰胆碱受体，由Chrna7编码）信号转导利用脾脏作为枢纽来抑制全身性炎症反应。迷走神经支配也延伸至远端气道和肺泡。迷走神经切断和α7nAChR缺乏会恶化大肠杆菌和脂多糖（LPS）诱导的急性肺部炎症反应;但是，基本机制仍然难以捉摸。在这里，我们假设迷走神经回路会限制脾脏的释放和肺对α7nAChR + CD11b + 细胞的募集（CD11b由Itgam编码，Itgam是单核细胞和中性粒细胞的表面标记）通过AKT1的磷酸化，该过程将确定肺损伤的严重程度。使用大肠杆菌和LPS诱导的肺损伤小鼠模型，我们发现迷走神经切断术增强了脾脏出口和α7nAChR + CD11b + 细胞的肺募集，从而使肺恶化炎症反应。用α7nAChR激动剂挽救迷走神经，保留了脾脏中的α7nAChR + CD11b + 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α7nAChR产生的迷走神经信号促进了α7nAChR + CD11b + 细胞中AKT1的丝氨酸473磷酸化，并使这些细胞稳定在脾脏中。 Akt1的缺失增强了脾脏的出口，并增强了α7nAChR + CD11b + 细胞的肺募集，引起中性粒细胞浸润的肺部炎症和损伤。 Chrna7和Itgam的迷走神经切断和双重缺失减少了脾脏和BAL（支气管肺泡灌洗）Ly6C int Gr1 hi 中性粒细胞和Ly6C hi 单核细胞，它们有助于将中性粒细胞和单核细胞募集到大肠杆菌损伤的肺部空域。 Chrna7和Itgam的双重缺失增加了肺对单核细胞和/或中性粒细胞的募集，并恶化了大肠杆菌和LPS诱导的肺损伤。因此，与α7nAChR + CD11b CD + + sup>细胞中的AKT1结合的迷走回路的信号减弱了大肠杆菌和LPS诱导的急性肺炎性反应。靶向该信号传导途径可以为治疗急性肺损伤提供新的治疗策略。

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