SIRT6 modulates lesion microenvironment in LPC induced demyelination by targeting astrocytic CHI3L1

Demyelination occurs widely in the central nervous system (CNS) neurodegenerative diseases, especially the multiple sclerosis (MS), which with a complex and inflammatory lesion microenvironment inhibiting remyelination. Sirtuin6 (SIRT6), a histone/protein deacetylase is of interest for its promising effect in transcriptional regulation, cell cycling, inflammation, metabolism and longevity. Here we show that SIRT6 participates in the remyelination process in mice subjected to LPC-induced demyelination. Using pharmacological SIRT6 inhibitors or activators, RNA sequencing analysis of the corpus callosum tissues further revealed that SIRT6 is involved in the regulation of glial activation during remyelination, with significant alterations observed in CHI3L1, a glycoprotein specifically secreted by astrocytes. Collectively, our data elucidate the role of SIRT6 in remyelination and further reveal astrocytic SIRT6/CHI3L1 as the key regulator for improving the remyelination environment, which may be a potential target for MS therapy.