Cui Huan, Sun Fengrun, Yu Ning, Cao Yan, Wang Xue, Zhang Di, Chen Zhen, Wang Naili, Yuan Bo, Liu Penghao, Duan Wanru, Qiu Wenying, Yin Xiangsha, Ma Chao
State Key Laboratory of Common Mechanism Research for Major Diseases, Department of Human Anatomy, Histology and Embryology, Neuroscience Center, Joint Laboratory of Anesthesia and Pain, Institute of Basic Medical Sciences Chinese Academy of Medical Sciences, School of Basic Medicine Peking Union Medical College, No.5 DongDanSanTiao, Dongcheng District, Beijing 100005, China.
National Human Brain Bank for Development and Function, Beijing, China.
iScience. 2024 Sep 24;27(10):111027. doi: 10.1016/j.isci.2024.111027. eCollection 2024 Oct 18.
Pain has become a major symptom of long COVID-19 without effective therapy. Apart from viral infection pathological process, SARS-CoV-2 membranal proteins (envelope [S2E], spike [S2S] and membrane [S2M]) also present pro-inflammatory feature independently. Here, we aim to uncover the neuroinflammatory mechanism of COVID-pain induced by SARS-CoV-2 membranal proteins. We detected the three proteins in both peripheral sensory ganglions and spinal dorsal horn of COVID-19 donors. After intradermal and intrathecal injection, only S2E triggered pain behaviors, accompanied with upregulated-phosphorylation nuclear factor kappa B (NF-κB), which was significantly attenuated by minocycline in mice. We further identified Toll-like receptor 2 (TLR2) among TLRs as the target of S2E to evoke inflammatory responses leading to COVID-pain. This study identified the nociceptive effect of S2E through directly interacting with macrophage/microglia TLR2 and inducing the following NF-κB inflammatory storm. Clearing away S2E and inhibiting macrophage/microglia TLR2 served as perspective therapeutic strategies for COVID-19 pain.
疼痛已成为长期新冠病毒感染的主要症状，却没有有效的治疗方法。除了病毒感染的病理过程外，严重急性呼吸综合征冠状病毒2（SARS-CoV-2）的膜蛋白（包膜蛋白[S2E]、刺突蛋白[S2S]和膜蛋白[S2M]）也独立呈现促炎特征。在此，我们旨在揭示由SARS-CoV-2膜蛋白诱导的新冠疼痛的神经炎症机制。我们在新冠病毒感染捐赠者的外周感觉神经节和脊髓背角中检测到了这三种蛋白。皮内和鞘内注射后，只有S2E引发疼痛行为，并伴有磷酸化核因子κB（NF-κB）上调，而米诺环素在小鼠中可显著减轻这种上调。我们进一步确定Toll样受体2（TLR2）是Toll样受体（TLRs）中S2E引发炎症反应导致新冠疼痛的靶点。本研究通过S2E直接与巨噬细胞/小胶质细胞TLR2相互作用并诱导随后的NF-κB炎症风暴，确定了S2E的伤害感受作用。清除S2E并抑制巨噬细胞/小胶质细胞TLR2是治疗新冠疼痛的潜在治疗策略。
