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 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.

Screening key genes and signaling pathways in COVID-19 infection and its associated complications by integrated bioinformatics analysis

“…In the present investigation, a total of 738 DEGs between COVID-19 samples and non COVID-19 samples were identified, consisting of 415 [76], SIGLEC1 [77] and IL1R2 [78] have been suggested to be associated with neurological diseases. CXCL9 [79], SIGLEC1 [80], IL1R2 [81], KLF15 [82] and CD207 [83] [146], STAT4 [147], CXCL8 [148], KLF2 [149], ADM (adrenomedullin) [150], EGR1 [151], TRIB1 [152], SOD2 [153] [162], PTEN (phosphatase and tensin homolog) [163], FOXO3 [164], DDIT4 [165], PINK1 [166], IQGAP1 [167], ADIPOR1 [168], MTMR3 [169] [464], IFNG (interferon gamma) [465], IFIH1 [466], STAT1 [467], CCR5 [468], ADCY5 [469], MT2A [470], DPP4 [471], FASLG (Fas ligand) [472], HLA-DMB [473], CD3D [474], CMKLR1 [475], ICOS (inducible T cell costimulator) [476] [492], CFB (complement factor B) [493], TLR7 [494], SLAMF1 [495], BPIFA1 [496], CD300E [497], TAP2 [498], CD48 [499], APOL1 [500], BACH2 [501], CD226 [502], CXCL12…”

Relationship between pyroptosis-mediated inflammation and the pathogenesis of prostate disease

“…AIM2 inflammasome can be activated by damaged double-stranded DNA, causing the release of inflammatory factors and GSDMD mediated pyroptosis ( 24 ). While cytoplasmic dsDNA/AIM2-associated pyroptosis leads to macrophage dysfunction ( 25 ). Although pyroptosis is an important link in many diseases, the AIM2 inflammasome as a trigger of pyroptosis has not attracted enough attention.…”

Diabetes mellitus: Lessons from COVID-19 for monkeypox infection

“…The expression of AIM2 was enhanced in diabetic and aging conditions and correlated with the inflammatory state. However, importantly metformin was shown to alleviate macrophage dysfunction in an AIM2-dependent manner [58] . The cGAS-cGAMP-STING pathway has been associated with chronic inflammation and obesity-induced insulin resistance [59] .…”