Lysine-specific demethylase 6B promotes STAT1-mediated macrophages activation during atherosclerosis development

Atherosclerosis (AS) induced coronary heart disease is still the first killer threatening human health due to high morbidity and mortality. How N6-methyladenosine modification (m6A) in macrophage participates in atherosclerosis progression is still completely unclear. In this study, by performing meRIP-seq in macrophages during differentiation and activation processes, we aim to understand the landscape of m6A spectrum in macrophage from different stages. Moreover, we also find a large class of histone methylation modification enzymes were regulated by m6A modification. Western blot, qPCR and ChIP-seq results demonstrate m6A modification regulates Lysine-specific demethylase 6B (Kdm6b)-dependent macrophage activation. In mechanism, Kdm6b interacts and methylates Jak1 inducing its phosphorylation-mediated macrophage activation. Furthermore, RIP-qPCR detection indicates following macrophage differentiation and activation, both m6A writers Mettl3 and Rbm15 participates in m6A modification of Kdm6b mRNA. Finally, by performing atherosclerotic model on macrophage-specific Kdm6b knockout mice on Ldlr-/- background, we demonstrate Kdm6b promotes macrophage activation-mediated atherosclerosis by amplifying inflammation and destabilizing plaque. This study will provide a new understanding of the pathogenesis of AS and is expected to develop a new target for the treatment of AS.