Dalli Jesmond, Colas Romain A, Arnardottir Hildur, Serhan Charles N
Center for Experimental Therapeutics and Reperfusion Injury, Harvard Institutes of Medicine, Department of Anesthesiology, Perioperative and Pain Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, USA; Lipid Mediator Unit, Centre for Biochemical Pharmacology, William Harvey Research Institute, Barts and the London School of Medicine, Queen Mary University of London, London EC1M 6BQ, UK.
Center for Experimental Therapeutics and Reperfusion Injury, Harvard Institutes of Medicine, Department of Anesthesiology, Perioperative and Pain Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, USA; Lipid Mediator Unit, Centre for Biochemical Pharmacology, William Harvey Research Institute, Barts and the London School of Medicine, Queen Mary University of London, London EC1M 6BQ, UK.
Immunity. 2017 Jan 17;46(1):92-105. doi: 10.1016/j.immuni.2016.12.009. Epub 2017 Jan 5.
Uncovering mechanisms that control immune responses in the resolution of bacterial infections is critical for the development of new therapeutic strategies that resolve infectious inflammation without unwanted side effects. We found that disruption of the vagal system in mice delayed resolution of Escherichia coli infection. Dissection of the right vagus decreased peritoneal group 3 innate lymphoid cell (ILC3) numbers and altered peritoneal macrophage responses. Vagotomy resulted in an inflammatory peritoneal lipid mediator profile characterized by reduced concentrations of pro-resolving mediators, including the protective immunoresolvent PCTR1, along with elevated inflammation-initiating eicosanoids. We found that acetylcholine upregulated the PCTR biosynthetic pathway in ILC3s. Administration of PCTR1 or ILC3s to vagotomized mice restored tissue resolution tone and host responses to E. coli infections. Together these findings elucidate a host protective mechanism mediated by ILC3-derived pro-resolving circuit, including PCTR1, that is controlled by local neuronal output to regulate tissue resolution tone and myeloid cell responses.
揭示在细菌感染消退过程中控制免疫反应的机制对于开发新的治疗策略至关重要，这些策略能够解决感染性炎症且无不良副作用。我们发现，小鼠迷走神经系统的破坏会延迟大肠杆菌感染的消退。切断右侧迷走神经会减少腹膜第3组固有淋巴细胞（ILC3）的数量，并改变腹膜巨噬细胞的反应。迷走神经切断术导致腹膜脂质介质谱呈现炎症特征，其特点是促消退介质浓度降低，包括具有保护作用的免疫溶解剂PCTR1，同时引发炎症的类花生酸水平升高。我们发现乙酰胆碱上调了ILC3中PCTR的生物合成途径。给迷走神经切断术小鼠施用PCTR1或ILC3可恢复组织消退张力以及宿主对大肠杆菌感染的反应。这些发现共同阐明了一种由ILC3衍生的促消退回路（包括PCTR1）介导的宿主保护机制，该机制受局部神经元输出控制，以调节组织消退张力和髓样细胞反应。
