Abstract
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 in vivo Moreover, in vitro, 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.
Highlights
Inflamm-aging was recently affiliated with the progression of diabetic complications
Immunohistochemical (IHC) staining of gingival tissue revealed that the p16positive and p21-positive cells gradually increased from weeks 9 to 17 and significantly increased from weeks 11 to 17 under ϳ30 mM blood glucose in diabetic mice compared with the control (Fig. 1D)
We investigated the biological mechanism by which hyperglycemia aggravated the inflamm-aging of macrophages in gingival tissue via NLRC4 phosphorylation and induced a high local burden of senescent cells and the secretion of senescence-associated secretory phenotype (SASP) factors
Summary
Inflamm-aging was recently affiliated with the progression of diabetic complications. 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. Hyperglycemia elevated the local burden of senescent cells in gingival tissue and induced the serum secretion of SASP factors in vivo. Deletion of NLRC4 or IRF8 abolished hyperglycemia-induced cellular senescence and SASP in macrophages. 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. Cellular senescence is crucial in the acquisition of the SASP, which mediates tissue dysfunction through a chronic secretion of proinflammatory cytokines, leading to diabetic complications (10 – 12). The senescent cell burden in tissue and SASP may directly contribute to diabetes-related gingival dysfunction and susceptibility to periodontal pathogens infection. The activation of NLRC4 in diabetes may induce cell senescence and SASP in gingiva
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