Diabetes fuels periodontal lesions via GLUT1-driven macrophage inflammaging

摘要

Hyperglycemia induces chronic low-grade inflammation(inflammaging),which is a newly identified contributor to diabetes-related tissue lesions,including the inflammatory bone loss in periodontitis.It is also a secondary senescent pattern mediated by an increased burden of senescent cells and senescence-associated secretory phenotype(SASP).Macrophage is a key SASPspreading cell and may contribute to the maintenance of SASP response in the periodontal microenvironment.Using a transgenic diabetic model(BLKS/J-Lepr^(db)/lepr^(db)mice)we identified striking senescence of the periodontium in young(18-wk)-diabetic mice accompanied by amassed p16^(+)-macrophages and enhanced early SASP response.Exposed to high glucose in vitro,bone marrow-derived macrophage(BMDM)revealed a strong GLUT1 m RNA response driving the elevated-glucose uptake.GLUT1 is a representative and facilitative glucose transporter in macrophages with potential roles in hyperglycemia-induced inflammation.In this study,both GLUT1 and the downstream GTPase Rheb expression upregulated in the gingiva of diabetic mice with impaired condition.Furthermore,SASP release and p16/p21 signaling were proven to be triggered by m TOR phosphorylation in BMDM and antagonized by restricting glucose uptake in GLUT1^(-/-)BMDM.Taken together,our findings suggest that elevated-GLUT1 sensor responded to high glucose is important for macrophage senescence and SASP response,generated as a result of hyperglycemia,and it is a potential molecular mechanism for the exacerbation of periodontitis in diabetes.