Neutralization of Hv1/HVCN1 With Antibody Enhances Microglia/Macrophages Myelin Clearance by Promoting Their Migration in the Brain

Abstract

Microglia dynamically monitor the microenvironment of the central nervous system (CNS) by constantly extending and retracting their processes in physiological conditions, and microglia/macrophages rapidly migrate into lesion sites in response to injuries or diseases in the CNS. Consequently, their migration ability is fundamentally important for their proper functioning. However, the mechanisms underlying their migration have not been fully understood. We wonder whether the voltage-gated proton channel HVCN1 in microglia/macrophages in the brain plays a role in their migration. We show in this study that in physiological conditions, microglia and bone marrow derived macrophage (BMDM) express HVCN1 with the highest level among glial cells, and upregulation of HVCN1 in microglia/macrophages is presented in multiple injuries and diseases of the CNS, reflecting the overactivation of HVCN1. In parallel, myelin debris accumulation occurs in both the focal lesion and the site where neurodegeneration takes place. Importantly, both genetic deletion of the HVCN1 gene in cells in vitro and neutralization of HVCN1 with antibody in the brain in vivo promotes migration of microglia/macrophages. Furthermore, neutralization of HVCN1 with antibody in the brain in vivo promotes myelin debris clearance by microglia/macrophages. This study uncovers a new role of HVCN1 in microglia/macrophages, coupling the proton channel HVCN1 to the migration of microglia/macrophages for the first time.