AZGP1 Aggravates Macrophage M1 Polarization and Pyroptosis in Periodontitis

作者全名："Yang, S.; Yin, Y.; Sun, Y.; Ai, D.; Xia, X.; Xu, X.; Song, J."

作者地址："[Yang, S.; Yin, Y.; Sun, Y.; Ai, D.; Xu, X.; Song, J.] Chongqing Med Univ, Coll Stomatol, 426 Songshibei Rd, Chongqing, 401147, Peoples R China; [Yang, S.; Yin, Y.; Sun, Y.; Ai, D.; Xu, X.; Song, J.] Chongqing Key Lab Oral Dis & Biomed Sci, Chongqing, Peoples R China; [Yang, S.; Yin, Y.; Sun, Y.; Ai, D.; Xu, X.; Song, J.] Chongqing Municipal Key Lab Oral Biomed Engn Highe, Chongqing, Peoples R China; [Xia, X.] Chongqing Med Univ, Affiliated Hosp 2, Dept Endocrinol, Chongqing, Peoples R China"

通信作者："Xu, X; Song, J (通讯作者)，Chongqing Med Univ, Coll Stomatol, 426 Songshibei Rd, Chongqing, 401147, Peoples R China."

来源：JOURNAL OF DENTAL RESEARCH

ESI学科分类：CLINICAL MEDICINE

WOS号：WOS:001185698800001

JCR分区：Q1

影响因子：5.7

年份：2024

卷号：　

期号：　

开始页：　

结束页：　

文献类型：Article; Early Access

关键词：periodontal diseases; bone loss; inflammation; innate immunity; type 2 diabetes; regulated cell death

摘要："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."

基金机构："National Key R&D of Program of China [2022YFC2504200]; National Natural Science Foundation of China [U22A20314, 82101014, 81771082, 31971282]; China Postdoctoral Science Foundation [2021M700628]; Natural Science Foundation of Chongqing [CSTB2022NSCQ-BHX0632, cstc2021jcyj-bsh0005]"

基金资助正文："The authors disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: This work was supported by the National Key R & D of Program of China (grant No. 2022YFC2504200), National Natural Science Foundation of China (grant No. U22A20314, 82101014; 81771082; 31971282), China Postdoctoral Science Foundation (grant No. 2021M700628), and Natural Science Foundation of Chongqing (grant No. CSTB2022NSCQ-BHX0632; cstc2021jcyj-bsh0005)."