AZGP1 会加剧牙周炎中巨噬细胞 M1 的极化和脓毒血症。

Journal of dental research Pub Date : 2024-06-01 Epub Date: 2024-03-15 DOI:10.1177/00220345241235616
S Yang, Y Yin, Y Sun, D Ai, X Xia, X Xu, J Song
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引用次数: 0

摘要

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,而这种反应在 2 型糖尿病(T2DM)的情况下可能会加剧。越来越多的证据表明,巨噬细胞介导的炎症与正常和 T2DM 条件下牙周炎的发病机制密切相关。然而,其根本机制仍然难以捉摸。甲型-2-糖蛋白 1(AZGP1)是一种具有 MHC-I 结构域的糖蛋白,与炎症和代谢紊乱都有关系。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,AZGP1在牙周炎中增高,在伴有T2DM时进一步增高。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 在牙周中的过表达显著增强了牙周炎症和牙槽骨丧失,并伴随着 M1 巨噬细胞的升高和热蛋白沉积,而 Azgp1-/- 小鼠则表现出相反的效应。在受到脂多糖(LPS)或 LPS 和棕榈酸(PA)刺激的原发性骨髓衍生巨噬细胞中,Azgp1 的过表达或基因敲除分别显著上调或抑制了巨噬细胞 M1 标记和 NLR 家族含吡林域 3(NLRP3)/caspase-1 信号转导的关键成分的表达。此外,在LPS或LPS+PA刺激下,Azgp1表达的巨噬细胞的条件培养基诱导了人牙周韧带干细胞(hPDLSCs)更高的炎症激活和更低的成骨分化。此外,NLRP3或caspase-1抑制剂可挽救Azgp1过表达诱导的巨噬细胞M1极化和脓毒症升高以及对hPDLSCs的相关不利影响。总之,我们的研究阐明了AZGP1可通过NLRP3/casapse-1途径促进巨噬细胞M1极化和热凋亡,从而加重牙周炎,而这在T2DM相关牙周炎中表现得更为明显。这一发现加深了人们对AZGP1在牙周炎发病机制中作用的认识,并表明AZGP1是糖尿病对牙周炎症产生不良影响的关键环节。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
AZGP1 Aggravates Macrophage M1 Polarization and Pyroptosis in Periodontitis.

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.

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