Periodontal tissue destruction in periodontitis is a consequence of the host inflammatory response to periodontal pathogens, which could be aggravated in the presence of type 2 diabetes mellitus (T2DM). Accumulating evidence highlights the intricate involvement of macrophage-mediated inflammation in the pathogenesis of periodontitis under both normal and T2DM conditions. However, the underlying mechanism remains elusive. Alpha-2-glycoprotein 1 (AZGP1), a glycoprotein featuring an MHC-I domain, has been implicated in both inflammation and metabolic disorders. In this study, we found that AZGP1 was primarily colocalized with macrophages in periodontitis tissues. AZGP1 was increased in periodontitis compared with controls, which was further elevated when accompanied by T2DM. Adeno-associated virus-mediated overexpression of Azgp1 in the periodontium significantly enhanced periodontal inflammation and alveolar bone loss, accompanied by elevated M1 macrophages and pyroptosis in murine models of periodontitis and T2DM-associated periodontitis, while Azgp1-/- mice exhibited opposite effects. In primary bone marrow–derived macrophages stimulated by lipopolysaccharide (LPS) or LPS and palmitic acid (PA), overexpression or knockout of Azgp1 markedly upregulated or suppressed, respectively, the expression of macrophage M1 markers and key components of the NLR Family Pyrin Domain Containing 3 (NLRP3)/caspase-1 signaling. Moreover, conditioned medium from Azgp1-overexpressed macrophages under LPS or LPS+PA stimulation induced higher inflammatory activation and lower osteogenic differentiation in human periodontal ligament stem cells (hPDLSCs). Furthermore, elevated M1 polarization and pyroptosis in macrophages and associated detrimental effects on hPDLSCs induced by Azgp1 overexpression could be rescued by NLRP3 or caspase-1 inhibition. Collectively, our study elucidated that AZGP1 could aggravate periodontitis by promoting macrophage M1 polarization and pyroptosis through the NLRP3/casapse-1 pathway, which was accentuated in T2DM-associated periodontitis. This finding deepens the understanding of AZGP1 in the pathogenesis of periodontitis and suggests AZGP1 as a crucial link mediating the adverse effects of diabetes on periodontal inflammation.

中文翻译：

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AZGP1 加剧牙周炎中巨噬细胞 M1 极化和焦亡

牙周炎中的牙周组织破坏是宿主对牙周病原体的炎症反应的结果，在 2 型糖尿病 (T2DM) 的存在下，这种炎症反应可能会加剧。越来越多的证据强调了巨噬细胞介导的炎症在正常和 T2DM 条件下牙周炎的发病机制中的复杂参与。然而，潜在的机制仍然难以捉摸。 Alpha-2-糖蛋白 1 (AZGP1) 是一种具有 MHC-I 结构域的糖蛋白，与炎症和代谢紊乱有关。在这项研究中，我们发现 AZGP1 主要与牙周炎组织中的巨噬细胞共定位。与对照组相比，牙周炎患者的 AZGP1 升高，当伴有 T2DM 时，AZGP1 进一步升高。在牙周炎和 T2DM 相关牙周炎的小鼠模型中，腺相关病毒介导的 Azgp1 在牙周组织中的过度表达显着增强了牙周炎症和牙槽骨丢失，并伴有 M1 巨噬细胞升高和焦亡。-/-小鼠表现出相反的效果。在脂多糖（LPS）或LPS和棕榈酸（PA）刺激的原代骨髓源性巨噬细胞中，Azgp1的过表达或敲除分别显着上调或抑制，巨噬细胞M1标记物和NLR家族Pyrin结构域的关键成分的表达3 (NLRP3)/caspase-1 信号传导。此外，来自Azgp1过表达巨噬细胞的条件培养基在LPS或LPS+PA刺激下诱导人牙周膜干细胞（hPDLSC）更高的炎症激活和更低的成骨分化。此外，巨噬细胞中 M1 极化和焦亡的升高以及 Azgp1 过表达诱导的 hPDLSC 的相关有害影响可以通过 NLRP3 或 caspase-1 抑制来挽救。总的来说，我们的研究阐明了 AZGP1 可以通过 NLRP3/casapse-1 通路促进巨噬细胞 M1 极化和焦亡，从而加重牙周炎，这在 T2DM 相关牙周炎中更为严重。这一发现加深了人们对AZGP1在牙周炎发病机制中的认识，并提示AZGP1是介导糖尿病对牙周炎症不良影响的关键环节。