VEGFR-3 signaling restrains the neuron-macrophage crosstalk during neurotropic viral infection

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 alpha (TNF-alpha) secretion to reduce neuron apoptosis. Vegfr-(3 Delta LBD/Delta LBD) (deletion of ligand-binding domain in myeloid cells) mice or mice treated with the VEGFR-3 kinase inhibitor exacerbate the severity of encephalitis, TNF-a production, and neuron apoptosis post Japanese encephalitis virus (JEV) infection. Activating VEGFR-3 or blocking TNF-alpha 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.

Automated summary

Using murine models, we found that vascular endothelial growth factor receptor 3 (VEGFR-3) is upregulated in macrophages in the central nervous system (CNS) upon viral infection, while infected neurons secrete the ligand VEGF-C. VEGFR-3(+) macrophages, when cultured with VEGF-C-containing supernatants from infected neurons, suppress tumor necrosis factor alpha (TNF-α) secretion to reduce neuron apoptosis. In mice treated with the VEGFR-3 kinase inhibitor or lacking the ligand-binding domain in myeloid cells, the severity of encephalitis, TNF-α production, and neuron apoptosis post Japanese encephalitis virus (JEV) infection worsens. Activating VEGFR-3 or blocking TNF-α can alleviate encephalitis and neuronal damage upon JEV infection.