Microglia Promote Lymphangiogenesis Around the Spinal Cord Through VEGF-C/VEGFR3-Dependent Autophagy and Polarization After Acute Spinal Cord Injury

Reducing secondary injury is a key focus in the field of spinal cord injury (SCI). Recent studies have revealed the role of lymphangiogenesis in reducing secondary damage to central nerve. However, the mechanism of lymphangiogenesis is not yet clear. Macrophages have been shown to play an important role in peripheral tissue lymphangiogenesis. Microglia is believed to play a role similar to macrophages in the central nervous system (CNS); we hypothesized that there was a close relationship between microglia and central nerve system lymphangiogenesis. Herein, we used an in vivo model of SCI to explored the relationship between microglia and spinal cord lymphangiogenesis and further investigated the polarization of microglia and its role in promoting spinal cord lymphangiogenesis by a series of in vitro experiments. The current study elucidated for the first time the relationship between microglia and lymphangiogenesis around the spinal cord after SCI. Classical activated (M1) microglia can promote lymphangiogenesis by secreting VEGF-C which further increases polarization and secretion of lymphatic growth factor by activating VEGFR3. The VEGF-C/VEGFR3 pathway activation downregulates microglia autophagy, thereby regulating the microglia phenotype. These results indicate that M1 microglia promote lymphangiogenesis after SCI, and activated VEGF-C/VEGFR3 signaling promotes M1 microglia polarization by inhibiting autophagy, thereby facilitates lymphangiogenesis.