迷走神经影响肺部微环境调控流感病毒感染、炎症和免疫反应

The pathogenesis of influenza A virus (IAV)-induced acute lung injury (ALI) is still unclear and its mortality remains high. How nervous system regulates infection, inflammation and immunity is a recent hotspot of research in the life science. Previously, we have found that vagus nerve could regulate pulmonary microenvironment via acetylcholine which activates α7 nicotinic acetylcholine receptor (α7 nAChR), therefore modulates acid aspiration or Gram negative bacteria-induced ALI. Here, we hypothesize that activity of vagus nerve would regulate lung microenvironment during IAV infection and consequently affect IAV replication and pulmonary inflammation and immunity. As such, we aim to study several key scientific questions: whether vagus nerve via α7 nAChR would regulate recognition and clearance of IAV in the lung epithelial and immune cells, affect induction of IFN-β and activity of ISRE, play a role in the M2 polarization of macrophages, have an impact on lung immune metabolism, and influence the recruitment or induction of lymphocytes or innate lymphoid cells during IAV-induced ALI, etc. To approach this, we will utilize molecular biological, immunological, neurophysiological and other advanced approaches. The ultimate goal is to understand how vagus nerve through α7 nAChR regulates pulmonary microenvironment and determines the outcome of IAV-induced ALI. The findings will provide us novel therapeutic targets for treating IAV-induced ALI.

流感病毒诱发急性肺损伤发病的分子机制尚不清楚，死亡率仍居高不下。神经对感染、炎症和免疫的调控是近年来生命科学领域的研究热点。既往我们研究发现迷走神经可释放乙酰胆碱调控肺部微环境并通过α7 nAChR影响酸吸入和细菌感染诱发的急性肺损伤。据此，我们假设迷走神经活性可以影响流感病毒感染时肺部微环境进而影响肺部的区域免疫。我们要探讨是否迷走神经可以通过α7 nAChR影响肺上皮细胞、免疫细胞对流感病毒的识别和清除？是否影响上述细胞IFN-β的诱导以及ISRE活性？是否影响巨噬细胞M2型极化？是否影响肺部免疫代谢？是否影响肺部淋巴细胞和天然淋巴样细胞的募集或诱导等科学问题？因此，我们将应用分子生物学、免疫学、神经生理学等先进手段来深入研究迷走神经如何调控肺部微环境，并通过α7 nAChR影响流感病毒肺部感染、炎症和免疫的分子机制。研究成果将为流感病毒诱发的急性肺损伤治疗提供新靶点。

流感病毒诱发急性肺损伤发病的分子机制尚不清楚，死亡率仍居高不下。神经对感染、炎症和免疫的调控是近年来生命科学领域的研究热点。既往我们研究发现迷走神经可释放乙酰胆碱调控肺部微环境并通过α7 nAChR影响酸吸入和细菌感染诱发的急性肺损伤。..据此，我们假设迷走神经活性可以影响流感病毒感染时肺部微环境进而影响肺部的区域免疫。我们要探讨是否迷走神经可以通过α7 nAChR影响肺上皮细胞、免疫细胞对流感病毒的识别和清除？是否影响上述细胞IFN-β的诱导以及ISRE活性？是否影响巨噬细胞M2型极化？是否影响肺部免疫代谢？是否影响肺部淋巴细胞和天然淋巴样细胞的募集或诱导等科学问题？..因此，我们将应用分子生物学、免疫学、神经生理学等先进手段来深入研究迷走神经如何调控肺部微环境，并通过α7 nAChR影响流感病毒肺部感染、炎症和免疫的分子机制。..我们发现1）在肺上皮细胞，迷走神经递质乙酰胆碱（ACh）激活α7 nAChR，募集PTP1B，活化NEDD4使其泛素化ASK1，减少p38MAPK磷酸化，减少CRM1对流感病毒vRNP的转运。2）在巨噬细胞，激活α7 nAChR促进pSTAT6结合Arg1启动子，减少FOXO1出核，解除IL-4诱导Arg1转录诱发的组蛋白H3K27Me3甲基化，进而促进巨噬细胞的II型极化。3）发现敲除α7 nAChR可以抑制显著抑制博来霉素诱导的肺纤维化形成（Sun, et al. Mol Med, 2017）。..该研究成果将为流感病毒诱发的急性肺损伤治疗提供新的治疗靶点，也为新生学科-电生物医学（Electrical Biomedicine）对疾病的治疗提供理论基础。