SIRT6-regulated macrophage efferocytosis epigenetically controls inflammation resolution of diabetic periodontitis

作者：Bang Li, Zhili Xin, Shiyu Gao, Yangjie Li, Songsong Guo, Yu Fu, Rongyao Xu, Dongmiao Wang, Jie Cheng, Laikui Liu, Ping Zhang, Hongbing Jiang · 发表于：Theranostics · 年份：2022 · DOI：10.7150/thno.78878 · 被引用次数：108 · 研究领域：Oral microbiology and periodontitis research、Immune cells in cancer、Heme Oxygenase-1 and Carbon Monoxide

Rationale: Diabetes exacerbates the prevalence and severity of periodontitis, leading to severe periodontal destruction and ultimately tooth loss. Delayed resolution of inflammation is a major contributor to diabetic periodontitis (DP) pathogenesis, but the underlying mechanisms of this imbalanced immune homeostasis remain unclear. Methods: We collected periodontium from periodontitis with or without diabetes to confirm the dysfunctional neutrophils and macrophages in aggravated inflammatory damage and impaired inflammation resolution. Our in vitro experiments confirmed that SIRT6 inhibited macrophage efferocytosis by restraining miR-216a-5p-216b-5p-217 cluster maturation through ''non-canonical'' microprocessor complex (RNA pulldown, RIP, immunostaining, CHIP, Luciferase assays, and FISH). Moreover, we constructed m6SKO mice that underwent LIP-induced periodontitis to explore the in vitro and in vivo effect of SIRT6 on macrophage efferocytosis. Finally, antagomiR-217, a miRNA antagonism, was delivered into the periodontium to treat LIP-induced diabetic periodontitis. Results: We discovered that insufficient SIRT6 as a histone deacetylase in macrophages led to unresolved inflammation and aggravated periodontitis in both human and mouse DP with accumulated apoptotic neutrophil (AN) and higher generation of neutrophil extracellular traps. Mechanistically, we validated that macrophage underwent high glucose stimulation resulting in disturbance of the SIRT6-miR-216/217 axis that ...