Liu Weiwei, Wang Si, Wang Jia, Zheng Rui, Wang Dalu, Yu Rui, Liu Beixing
Department of Pathogenic Microbiology, School of Basic Medical Science, China Medical University, Shenyang, China.
Department of Anesthesiology, The First Hospital of China Medical University, Shenyang, China; and.
Am J Respir Cell Mol Biol. 2023 Mar;68(3):256-266. doi: 10.1165/rcmb.2022-0123OC.
Activated group 2 innate lymphoid cells (ILC2s) play a crucial role in respiratory syncytial virus (RSV)-induced airway inflammation and allergy-like symptoms because of their ability to secrete large quantities of type 2 cytokines. Cytokines such as IL-33, IL-25, and thymic stromal lymphopoietin are activators of ILC2s. Besides, a regulatory effect of neurotransmitters on ILC2 activation has been reported recently. However, whether and how RSV infection induces neurotransmitter production in the lungs and regulates pulmonary ILC2 activation remains unclear. In this study, using a murine model established by intranasal infection with RSV, we found that acute RSV infection induced the production of a neurotransmitter, neuromedin U (NMU), in the lungs of RSV-infected mice and upregulated the expression of NMUR1 (neuromedin U receptor 1) on ILC2s. Moreover, administration of NMU exacerbated RSV-induced airway inflammation by promoting the proliferation and activation of pulmonary ILC2s via the NMUR1 pathway, which involved PI3K, mitogen-activated protein kinase kinase, and NFAT signaling proteins. Furthermore, pulmonary neurons responded to the stimulation of RSV infection and secreted NMU in a Toll-like receptor 4- and Toll-like receptor 7-dependent manner. Collectively, our data suggest that NMU is a powerful neuropeptide to activate ILC2s, highlighting the critical regulatory effects of neurotransmitters on antiviral, inflammatory, and tissue homeostasis at the mucosal barrier during a viral respiratory infection.
活化的2型固有淋巴细胞（ILC2s）在呼吸道合胞病毒（RSV）诱导的气道炎症和类过敏症状中起关键作用，因为它们能够分泌大量的2型细胞因子。IL-33、IL-25和胸腺基质淋巴细胞生成素等细胞因子是ILC2s的激活剂。此外，最近有报道称神经递质对ILC2激活具有调节作用。然而，RSV感染是否以及如何诱导肺中神经递质的产生并调节肺部ILC2激活仍不清楚。在本研究中，我们使用经鼻感染RSV建立的小鼠模型，发现急性RSV感染可诱导RSV感染小鼠肺中神经递质神经介素U（NMU）的产生，并上调ILC2s上神经介素U受体1（NMUR1）的表达。此外，给予NMU可通过NMUR1途径促进肺部ILC2s的增殖和激活，从而加剧RSV诱导的气道炎症，该途径涉及PI3K、丝裂原活化蛋白激酶激酶和NFAT信号蛋白。此外，肺神经元对RSV感染的刺激作出反应，并以Toll样受体4和Toll样受体7依赖性方式分泌NMU。总的来说，我们的数据表明NMU是一种强大的神经肽，可激活ILC2s，突出了神经递质在病毒性呼吸道感染期间对粘膜屏障处的抗病毒、炎症和组织稳态的关键调节作用。
