VEGF-C Induces Alternative Activation of Microglia to Promote Recovery from Traumatic Brain Injury

Traumatic brain injury (TBI), a brain disorder that causes death and long-term disability in humans, is increasing in prevalence, though there is a lack of protective or therapeutic strategies for mitigating the damage after TBI and for preserving neurological functionality. Microglia cells play a key role in neuroinflammation following TBI, but their regulation and polarization by a member of the vascular endothelial growth factor (VEGF) family, VEGF-C, is unknown. Here, we show that VEGF-C induced M2 polarization in a murine microglia cell line, BV-2, in vitro, by a mechanism that required signaling from its unique receptor, VEGF receptor 3 (VEGFR3). Moreover, in a TBI model in rats, VEGF-C administration induced M2 polarization of microglia cells, significantly improved motor deficits after experimental TBI, and significantly improved neurological function following TBI, likely through a reduction in cell apoptosis. Together, our data reveal a previously unknown role of VEGF-C/VEGFR3 signaling in the regulation of post-TBI microglia cell polarization, which appears to be crucial for recovery from TBI.