Abstract
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 SASP-spreading cell and may contribute to the maintenance of SASP response in the periodontal microenvironment. Using a transgenic diabetic model (BLKS/J-Leprdb/leprdb 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 mRNA 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 mTOR 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.
Highlights
Diabetes mellitus is a recognized age-related disease,[1] and commonly is associated with chronic inflammatory bone loss in periodontitis whose pathogenesis is concerned with age.[2]
We focused on the role of inflammaging that occurred in diabetes on periodontal tissue damage, and investigated the potential mechanism of glucose transporter 1 (GLUT1) in hyperglycemia-induced macrophage senescence and senescence-associated secretory phenotype (SASP) response in the periodontal tissue
Hyperglycemia leads to a SASP response in the periodontium of diabetic mice To understand the reason that hyperglycemia aggravates periodontal damage, we started with a contrastive study in young (18-week-old) mice versus aged (20-month-old) mice treated with or without streptozotocin (STZ)
Summary
Diabetes mellitus is a recognized age-related disease,[1] and commonly is associated with chronic inflammatory bone loss in periodontitis whose pathogenesis is concerned with age.[2]. Inflammaging, the chronic low-grade inflammation that accompanies aging, is recently implicated in the pathogenesis of diabetes-related disorders.[4,5] During aging, cell senescence proceeds through an early senescent-response phase followed by the senescence-associated secretory phenotype (SASP) response.[5,6] It is recognized that a heavier burden of senescent cells (SCs) together with SASP in diabetes leads to tissue disruption.[7,8] The activity of Interleukin (IL)−1β represents the early SASP response,[9] one of the specific determinants of aging.[10,11]
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