TLR2/NF-κB signaling in macrophage/microglia mediated COVID-pain induced by SARS-CoV-2 envelope protein
Huan Cui,
Fengrun Sun,
Ning Yu,
Yan Cao,
Xue Wang,
Di Zhang,
Zhen Chen,
Naili Wang,
Bo Yuan,
Penghao Liu,
Wanru Duan,
Wenying Qiu,
Xiangsha Yin,
Chao Ma
Affiliations
Huan Cui
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
Fengrun Sun
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
Ning Yu
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
Yan Cao
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
Xue Wang
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
Di Zhang
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
Zhen Chen
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
Naili Wang
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
Bo Yuan
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
Penghao Liu
Department of Neurosurgery, Xuanwu Hospital, Capital Medical University, Laboratory of Spinal Cord Injury and Functional Reconstruction, China International Neuroscience Institute (CHINA-INI), Beijing, China
Wanru Duan
Department of Neurosurgery, Xuanwu Hospital, Capital Medical University, Laboratory of Spinal Cord Injury and Functional Reconstruction, China International Neuroscience Institute (CHINA-INI), Beijing, China
Wenying Qiu
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; Corresponding author
Xiangsha Yin
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; Corresponding author
Chao Ma
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; Chinese Institute for Brain Research, Beijing 102206, China; Corresponding author
Summary: 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.
