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

ABSTRACT: 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.

ORGANISM(S): Mus musculus

PROVIDER: GSE271963 | GEO | 2025/07/31

REPOSITORIES: GEO

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Project description:Senescent foamy macrophages are the key pathogenic drivers of atherosclerosis (AS) progression and plaque stability. The RNA N6-methyladenosine (m6A) modification plays an important role in the development of various diseases. However, its role in foamy macrophage aging during AS is still not clarified. To assess m6A methylation levels and m6A modifying enzyme profiles, the infiltrated macrophages were sorted using CD68+ magnetic beads from plaque tissues of patients with AS and high-fat diet feeding Apoe-/- mice. The ALKBH5f/f, Lyz2Cre, Apoe-/- mice were constructed to observe senescent macrophage infiltrated in plaques and AS progression. The RNA-seq, MeRIP, RIP and dual luciferase assays were performed to explore the mechanisms of ALKBH5-mediated formation of senescent macrophage. Downregulated m6A methylation levels and upregulated ALKBH5 expression were observed in aortic plaques and infiltrated macrophages from AS patients and mice. Compared with control mice, ALKBH5f/f, Lyz2Cre, Apoe-/- mice decreased AS plaques and enhanced plaque stability by suppressing senescence of foamy macrophages and senescence-associated secretory phenotypes. In addition, the data of the RNA-seq, MeRIP, RIP and dual luciferase assays showed that ALKBH5 deletion reduced the mRNA level of CC chemokine ligand 5 (CCL5) by increased m6A methylation in macrophages. Actinomycin D assay indicated ALBH5 knockout destroyed stability of Ccl5 mRNA. Mechanismly, ALKBH5 promotes senescent macrophage formation by CCL5/CC chemokine receptor 5 (CCR5)/mTORC1/autophagy signaling. And ALKBH5 induced macrophage derived CCL5 recruits increasingly CD8+IFNγ+ T cells by CCL5-CCR5 axis. Furthermore, the application of ALKBH5 inhibitor IOX-1 and CCR5 monoclonal antibody Adaptavir are potential clinical interventions for the inhibition of senescent macrophage formation and AS progress. Myeloid ALKBH5 deletion mitigates AS progression by suppressing the formation of senescent macrophages and the recruitment of CD8+IFNγ+ T cells. These findings favour the ALKBH5/CCL5/CCR5 signaling as novel targets for atherosclerosis therapy.

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

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