Endothelin-1 as an Activator of Pro-inflammatory Microglia Cells in Multiple Sclerosis

Background: Multiple sclerosis (MS) is a neurodegenerative autoimmune disease characterized by inflammation, demyelination, and axonal degeneration. In MS patients, demyelination is associated with activated microglia. ET-1 is a potent vasoconstrictor that has been documented in MS. However, the mechanism of how ET-1 activates a proinflammatory response is unknown. Objective: Demonstrate that high levels of ET-1 contribute to the progression of MS. Methods: C57BL/6 mice were used with or without induced experimental autoimmune encephalomyelitis (EAE). The brain ET-1 levels were measured by qPCR and ELISA. HMC3 cells were treated with ET-1 in the presence or absence of endothelin receptor B antagonist, BQ788. Nitric Oxide (NO) and ROS were measured using Griess Reagent and MUSE Oxidative Stress kit. Results: ET-1 was upregulated in EAE mice. ET-1 levels were correlated with EAE score at onset. ET-1 increases TNF levels in HMC3 cells, and it was decreased by the BQ788. iNOS, NO, and ROS production are induced by ET-1 in HMC3 cells, and treatment with BQ788 decreases them. Conclusion: These data suggest that ET-1 was able to activate microglia, increasing inflammatory cytokines, NO, and ROS. This is a novel mechanism of microglial cell activation and will provide key information to understand MS pathogenesis.