State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu 610041, China; Department of Prosthodontics, West China Hospital of Stomatology, Sichuan University, Chengdu 610041, China.
State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu 610041, China.
J Biol Chem. 2019 Dec 6;294(49):18807-18819. doi: 10.1074/jbc.RA119.010648. Epub 2019 Nov 1.
Inflamm-aging was recently affiliated with the progression of diabetic complications. Local cellular senescence together with senescence-associated secretory phenotype (SASP) are the main contributors to inflamm-aging. However, little is known about their involvement in diabetic periodontitis. Gingiva is the first line of host defense in the periodontium, and macrophages are key SASP-carrying cells. Here, we explored the molecular mechanism by which hyperglycemia drives the inflamm-aging in the gingival tissue of diabetic mice and macrophages. We demonstrated that hyperglycemia increased the infiltrated macrophage senescence in gingival tissue of diabetic mice. Simultaneously, hyperglycemia elevated the local burden of senescent cells in gingival tissue and induced the serum secretion of SASP factors Moreover, , high glucose induced macrophage senescence and SASP factors secretion through phosphorylation of NLRC4, which further stimulated the NF-κB/Caspase-1 cascade via an IRF8-dependent pathway. Deletion of NLRC4 or IRF8 abolished hyperglycemia-induced cellular senescence and SASP in macrophages. In addition, we found that treatment with metformin inhibited NLRC4 phosphorylation and remarkably decreased cellular senescence and SASP in the context of hyperglycemia. Our data demonstrated that hyperglycemia induces the development of inflamm-aging in gingival tissue and suggested that NLRC4 is a potential target for treatment of diabetes-associated complications.
炎症性衰老最近与糖尿病并发症的进展有关。局部细胞衰老加上衰老相关分泌表型 (SASP) 是炎症性衰老的主要贡献者。然而，关于它们在糖尿病性牙周炎中的参与情况知之甚少。牙龈是牙周组织中宿主防御的第一道防线，巨噬细胞是 SASP 携带细胞的关键。在这里，我们探讨了高血糖驱动糖尿病小鼠和巨噬细胞牙龈组织中炎症性衰老的分子机制。我们证明了高血糖增加了糖尿病小鼠牙龈组织中浸润的巨噬细胞衰老。同时，高血糖增加了牙龈组织中衰老细胞的局部负担，并诱导 SASP 因子的血清分泌。此外，高糖通过 NLRC4 的磷酸化诱导巨噬细胞衰老和 SASP 因子的分泌，进而通过依赖 IRF8 的途径刺激 NF-κB/Caspase-1 级联反应。NLRC4 或 IRF8 的缺失消除了高糖诱导的巨噬细胞衰老和 SASP。此外，我们发现二甲双胍治疗抑制了 NLRC4 的磷酸化，并显著减少了高糖环境中细胞衰老和 SASP。我们的数据表明高血糖诱导了牙龈组织中炎症性衰老的发展，并表明 NLRC4 是治疗糖尿病相关并发症的潜在靶点。
