Department of Periodontics, The Affiliated Stomatological Hospital of Nanjing Medical University, Nanjing, China; Jiangsu Province Key Laboratory of Oral Diseases, Nanjing, China; Jiangsu Province Engineering Research Center of Stomatological Translational Medicine, Nanjing, China.
Exp Cell Res. 2022 Sep 1;418(1):113264. doi: 10.1016/j.yexcr.2022.113264. Epub 2022 Jun 15.
A20 is involved in inflammation and bone metabolism in periodontitis. Regulation of macrophage polarization may be an effective target for periodontitis treatment, and A20 has a regulatory role in macrophage polarization. This study aimed to explore the effects of A20 on macrophage polarization in periodontitis and the underlying mechanism. Adeno-associated virus (AAV) targeting A20 was exploited to achieve A20 knockdown or overexpression in periodontal tissues of mice with experimental periodontitis. The (AAV-A20-RNAi) +P group showed increased alveolar bone resorption when compared with PBS + P and CON305 + P groups. However, the degree of bone destruction was reduced in the (AAV-A20) +P group relative to PBS + P and CON299 + P groups. A20 knockdown resulted in enhanced inducible nitric oxide synthase (iNOS) expression and decreased CD206 expression in mice periodontal tissues. In addition, higher levels of M1 macrophage polarization markers (iNOS, CD86, TNF-α) and lower CD206 expression were found in THP-1 cells treated with lipopolysaccharide (LPS) from Porphyromonas gingivalis (P. gingivalis) (Pg. LPS) and interferon-γ (IFN-γ) when A20 was silenced. A20 overexpression showed opposite effects on macrophage polarization in vivo and in vitro. Knockdown of A20 was correlated with upregulation of the NLRP3 inflammasome pathway in mice periodontal tissues or THP-1 cells. On the contrary, A20 overexpression inhibited the NLRP3 inflammasome pathway. MCC950 suppressed M1 macrophage polarization aggravated through A20 knockdown in Pg. LPS and IFN-γ stimulated cells. Our data suggested that A20 inhibits periodontal bone resorption and NLRP3-mediated M1 macrophage polarization; A20 is expected to be a novel target for the treatment of periodontitis.
A20 参与了牙周炎中的炎症和骨代谢。调节巨噬细胞极化可能是牙周炎治疗的有效靶点，而 A20 在巨噬细胞极化中具有调节作用。本研究旨在探讨 A20 对牙周炎中巨噬细胞极化的影响及其潜在机制。利用靶向 A20 的腺相关病毒 (AAV) 在实验性牙周炎小鼠的牙周组织中实现 A20 的敲低或过表达。与 PBS+P 和 CON305+P 组相比，(AAV-A20-RNAi)+P 组显示出牙槽骨吸收增加。然而，与 PBS+P 和 CON299+P 组相比，(AAV-A20)+P 组的骨破坏程度降低。A20 敲低导致小鼠牙周组织中诱导型一氧化氮合酶 (iNOS) 表达增强和 CD206 表达降低。此外，在脂多糖 (LPS) 来自牙龈卟啉单胞菌 (P. gingivalis) (Pg. LPS) 和干扰素-γ (IFN-γ) 处理的 THP-1 细胞中，发现更高水平的 M1 巨噬细胞极化标志物 (iNOS、CD86、TNF-α) 和更低的 CD206 表达，当 A20 被沉默时。A20 过表达对体内和体外巨噬细胞极化具有相反的影响。A20 敲低与小鼠牙周组织或 THP-1 细胞中 NLRP3 炎性小体途径的上调相关。相反，A20 过表达抑制了 NLRP3 炎性小体途径。MCC950 抑制了通过 A20 敲低在 Pg. LPS 和 IFN-γ 刺激的细胞中加剧的 M1 巨噬细胞极化。我们的数据表明，A20 抑制牙周骨吸收和 NLRP3 介导的 M1 巨噬细胞极化；A20 有望成为牙周炎治疗的新靶点。
