The glycosyltransferase EXTL2 and its regulation of remyelination and neuroinflammation

Abstract

The extracellular matrix is an area that is poorly studied in the context of central nervous system (CNS) regeneration and inflammation. Previous works have demonstrated the chondroitin sulfate proteoglycans (CSPGs) to be a major group of matrix constituents that potently inhibit the growth of axons both during development and following injury. However, there are gross changes that occur in the composition of the matrix in injury, the full implications of which have yet to be elucidated. We use the lysolecithin-induced model of demyelination in mice to investigate the roles that CSPGs serve in remyelination and inflammation with respect to microglia and macrophages. We find that CSPGs are a mediator of microglia/macrophagemediated inflammation in the spinal cord, and loss of a regulatory enzyme, exostosin-like 2 (EXTL2), results in exacerbated neuroinflammation following injury. In culture, bone marrow-derived macrophages from EXTL2-/- animals produce more matrix metalloproteinase and tumor necrosis factor alpha when stimulated with CSPGs. The supernatant from these cells are also more neurotoxic to cultured neurons. Overall, this work highlights CSPGs as an important factor that influences inflammation in the CNS.