Diabetes induces macrophage dysfunction through cytoplasmic dsDNA/AIM2 associated pyroptosis

ABSTRACT: Diabetes is emerging as a severe global health problem that threatens health and increases socio-economic burden. Periodontal impairment is one of its well-recognized complication. 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 condition. Besides, we further explored the molecular mechanism of how the hyperglycemia and aging contributes 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 condition, 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 (SASP). Meanwhile, we found that expressions of GSDMD and caspase-1 were upregulated 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.

ORGANISM(S): Mus musculus

PROVIDER: GSE169536 | GEO | 2021/03/25

REPOSITORIES: GEO