Cell Reports (May 2023)
VEGFR-3 signaling restrains the neuron-macrophage crosstalk during neurotropic viral infection
- Linlin Qi,
- Xiaojing Li,
- Fang Zhang,
- Xingguo Zhu,
- Qi Zhao,
- Dan Yang,
- Shujie Hao,
- Tong Li,
- Xiangyue Li,
- Taikun Tian,
- Jian Feng,
- Xiaochen Sun,
- Xilin Wang,
- Shangyan Gao,
- Hanzhong Wang,
- Jing Ye,
- Shengbo Cao,
- Yulong He,
- Hongyan Wang,
- Bin Wei
Affiliations
- Linlin Qi
- Institute of Geriatrics, Affiliated Nantong Hospital of Shanghai University (The Sixth People’s Hospital of Nantong), School of Medicine, Shanghai University, Nantong 226011, China; Shanghai Engineering Research Center of Organ Repair, School of Life Sciences, Shanghai University, Shanghai 200444, China; State Key Laboratory of Virology, Wuhan Institute of Virology, Chinese Academy of Sciences, University of Chinese Academy of Sciences, Wuhan 430071, China
- Xiaojing Li
- Institute of Geriatrics, Affiliated Nantong Hospital of Shanghai University (The Sixth People’s Hospital of Nantong), School of Medicine, Shanghai University, Nantong 226011, China; Shanghai Engineering Research Center of Organ Repair, School of Life Sciences, Shanghai University, Shanghai 200444, China
- Fang Zhang
- Institute of Geriatrics, Affiliated Nantong Hospital of Shanghai University (The Sixth People’s Hospital of Nantong), School of Medicine, Shanghai University, Nantong 226011, China; State Key Laboratory of Virology, Wuhan Institute of Virology, Chinese Academy of Sciences, University of Chinese Academy of Sciences, Wuhan 430071, China; Cancer Center, Shanghai Tenth People’s Hospital, School of Medicine, Tongji University, Shanghai 200072, China
- Xingguo Zhu
- Institute of Geriatrics, Affiliated Nantong Hospital of Shanghai University (The Sixth People’s Hospital of Nantong), School of Medicine, Shanghai University, Nantong 226011, China; Shanghai Engineering Research Center of Organ Repair, School of Life Sciences, Shanghai University, Shanghai 200444, China
- Qi Zhao
- Institute of Geriatrics, Affiliated Nantong Hospital of Shanghai University (The Sixth People’s Hospital of Nantong), School of Medicine, Shanghai University, Nantong 226011, China; Shanghai Engineering Research Center of Organ Repair, School of Life Sciences, Shanghai University, Shanghai 200444, China
- Dan Yang
- State Key Laboratory of Virology, Wuhan Institute of Virology, Chinese Academy of Sciences, University of Chinese Academy of Sciences, Wuhan 430071, China
- Shujie Hao
- Institute of Geriatrics, Affiliated Nantong Hospital of Shanghai University (The Sixth People’s Hospital of Nantong), School of Medicine, Shanghai University, Nantong 226011, China; Shanghai Engineering Research Center of Organ Repair, School of Life Sciences, Shanghai University, Shanghai 200444, China
- Tong Li
- State Key Laboratory of Virology, Wuhan Institute of Virology, Chinese Academy of Sciences, University of Chinese Academy of Sciences, Wuhan 430071, China
- Xiangyue Li
- Institute of Geriatrics, Affiliated Nantong Hospital of Shanghai University (The Sixth People’s Hospital of Nantong), School of Medicine, Shanghai University, Nantong 226011, China; Shanghai Engineering Research Center of Organ Repair, School of Life Sciences, Shanghai University, Shanghai 200444, China
- Taikun Tian
- Institute of Geriatrics, Affiliated Nantong Hospital of Shanghai University (The Sixth People’s Hospital of Nantong), School of Medicine, Shanghai University, Nantong 226011, China; Shanghai Engineering Research Center of Organ Repair, School of Life Sciences, Shanghai University, Shanghai 200444, China
- Jian Feng
- Institute of Geriatrics, Affiliated Nantong Hospital of Shanghai University (The Sixth People’s Hospital of Nantong), School of Medicine, Shanghai University, Nantong 226011, China; Shanghai Engineering Research Center of Organ Repair, School of Life Sciences, Shanghai University, Shanghai 200444, China
- Xiaochen Sun
- Institute of Geriatrics, Affiliated Nantong Hospital of Shanghai University (The Sixth People’s Hospital of Nantong), School of Medicine, Shanghai University, Nantong 226011, China; Shanghai Engineering Research Center of Organ Repair, School of Life Sciences, Shanghai University, Shanghai 200444, China
- Xilin Wang
- Institute of Geriatrics, Affiliated Nantong Hospital of Shanghai University (The Sixth People’s Hospital of Nantong), School of Medicine, Shanghai University, Nantong 226011, China; Shanghai Engineering Research Center of Organ Repair, School of Life Sciences, Shanghai University, Shanghai 200444, China
- Shangyan Gao
- Institute of Geriatrics, Affiliated Nantong Hospital of Shanghai University (The Sixth People’s Hospital of Nantong), School of Medicine, Shanghai University, Nantong 226011, China
- Hanzhong Wang
- State Key Laboratory of Virology, Wuhan Institute of Virology, Chinese Academy of Sciences, University of Chinese Academy of Sciences, Wuhan 430071, China
- Jing Ye
- State Key Laboratory of Agricultural Microbiology, Huazhong Agricultural University, Wuhan 430070, China
- Shengbo Cao
- State Key Laboratory of Agricultural Microbiology, Huazhong Agricultural University, Wuhan 430070, China
- Yulong He
- Cyrus Tang Hematology Center, Collaborative Innovation Center of Hematology, State Key Laboratory of Radiation Medicine and Protection, Cam-Su Genomic Resources Center, Soochow University, Suzhou 215123, China
- Hongyan Wang
- State Key Laboratory of Cell Biology, Shanghai Institute of Biochemistry and Cell Biology, Center for Excellence in Molecular Cell Science, Chinese Academy of Sciences, University of Chinese Academy of Sciences, Shanghai 200031, China; School of Life Science, Hangzhou Institute for Advanced Study, University of Chinese Academy of Sciences, Hangzhou 310024, China; Corresponding author
- Bin Wei
- Institute of Geriatrics, Affiliated Nantong Hospital of Shanghai University (The Sixth People’s Hospital of Nantong), School of Medicine, Shanghai University, Nantong 226011, China; Shanghai Engineering Research Center of Organ Repair, School of Life Sciences, Shanghai University, Shanghai 200444, China; State Key Laboratory of Virology, Wuhan Institute of Virology, Chinese Academy of Sciences, University of Chinese Academy of Sciences, Wuhan 430071, China; Cancer Center, Shanghai Tenth People’s Hospital, School of Medicine, Tongji University, Shanghai 200072, China; Department of Laboratory Medicine, Gene Diagnosis Research Center, Fujian Key Laboratory of Laboratory Medicine, The First Affiliated Hospital, Fujian Medical University, Fuzhou 350000, China; Corresponding author
- Journal volume & issue
-
Vol. 42,
no. 5
p. 112489
Abstract
Summary: Upon recognizing danger signals produced by virally infected neurons, macrophages in the central nervous system (CNS) secrete multiple inflammatory cytokines to accelerate neuron apoptosis. The understanding is limited about which key effectors regulate macrophage-neuron crosstalk upon infection. We have used neurotropic-virus-infected murine models to identify that vascular endothelial growth factor receptor 3 (VEGFR-3) is upregulated in the CNS macrophages and that virally infected neurons secrete the ligand VEGF-C. When cultured with VEGF-C-containing supernatants from virally infected neurons, VEGFR-3+ macrophages suppress tumor necrosis factor α (TNF-α) secretion to reduce neuron apoptosis. Vegfr-3ΔLBD/ΔLBD (deletion of ligand-binding domain in myeloid cells) mice or mice treated with the VEGFR-3 kinase inhibitor exacerbate the severity of encephalitis, TNF-α production, and neuron apoptosis post Japanese encephalitis virus (JEV) infection. Activating VEGFR-3 or blocking TNF-α can reduce encephalitis and neuronal damage upon JEV infection. Altogether, we show that the inducible VEGF-C/VEGFR-3 module generates protective crosstalk between neurons and macrophages to alleviate CNS viral infection.
