State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, China.
Department of Prosthodontics, West China Hospital of Stomatology, Sichuan University, Chengdu, China.
J Leukoc Biol. 2021 Sep;110(3):497-510. doi: 10.1002/JLB.3MA0321-745R. Epub 2021 Jun 4.
Diabetes is emerging as a severe global health problem that threatens health and increases socioeconomic burden. Periodontal impairment is one of its well-recognized complications. The destruction of the periodontal defense barrier makes it easier for periodontal pathogens to invade in, triggering a greater inflammatory response, and causing secondary impairment. Macrophages are the major immune cells in periodontium, forming the frontier line of local innate immune barrier. Here, we explored the periodontal impairments and functional changes of macrophages under the diabetic and aging conditions. Besides, we further explored the molecular mechanism of how hyperglycemia and aging contribute to this pathogenesis. To test this, we used young and aged mice to build diabetic mice, and metformin treatment was applied to a group of them. We demonstrated that under hyperglycemia conditions, macrophage functions, such as inflammatory cytokines secretion, phagocytosis, chemotaxis, and immune response, were disturbed. Simultaneously, this condition elevated the local senescent cell burden and induced secretion of senescence-associated secretory phenotype. Meanwhile, we found that expressions of Gasdermin D (GSDMD) and caspase-1 were up-regulated in diabetic conditions, suggesting that the local senescent burden and systemic proinflammatory state during diabetes were accompanied by the initiation of pyroptosis. Furthermore, we found that the changes in aged condition were similar to those in diabetes, suggesting a hyperglycemia-induced pre-aging state. In addition, we show that metformin treatment alleviated and remarkably reversed these functional abnormalities. Our data demonstrated that diabetes initiated macrophage pyroptosis, which further triggered macrophage function impairments and gingival destructions. This pathogenesis could be reversed by metformin.
糖尿病正成为一个严重的全球健康问题，威胁着人们的健康并加重社会经济负担。牙周损伤是其公认的并发症之一。牙周防御屏障的破坏使牙周病原体更容易侵入，引发更大的炎症反应，并导致继发性损伤。巨噬细胞是牙周组织中的主要免疫细胞，构成局部固有免疫屏障的前沿。在这里，我们研究了糖尿病和衰老条件下牙周组织损伤和巨噬细胞功能变化。此外，我们还进一步探讨了高血糖和衰老导致这种发病机制的分子机制。为此，我们使用年轻和年老的小鼠构建糖尿病小鼠，并对其中一组应用二甲双胍进行治疗。我们发现，在高血糖条件下，巨噬细胞的功能，如炎症细胞因子的分泌、吞噬作用、趋化作用和免疫反应，受到干扰。同时，这种情况增加了局部衰老细胞负担，并诱导了衰老相关分泌表型的分泌。同时，我们发现糖尿病状态下 Gasdermin D (GSDMD) 和 caspase-1 的表达上调，表明糖尿病期间局部衰老负担和全身促炎状态伴随着细胞焦亡的启动。此外，我们发现衰老状态的变化与糖尿病相似，表明高血糖诱导的预衰老状态。此外，我们表明二甲双胍治疗可缓解并显著逆转这些功能异常。我们的数据表明，糖尿病引发了巨噬细胞细胞焦亡，进而触发了巨噬细胞功能损伤和牙龈破坏。这种发病机制可以通过二甲双胍逆转。
