BackgroundThe aryl hydrocarbon receptor (AhR) has been studied as an intracellular pattern recognition receptor that can identify bacterial pigments. To identify a potential therapeutic target for periodontitis, we investigated the expression of AhR in periodontitis and its role in the pathogenesis of periodontitis.MethodsFirst, we analyzed AhR expression in a single‐cell dataset from human periodontal tissue. Quantitative polymerase chain reaction (qPCR), immunofluorescence, and immunohistochemistry were used to verify the AhR level. Later, we determined the phenotypes of ligature‐induced periodontitis in myeloid‐specific AhR‐deficient mice (Lyz2‐Cre+/− AhRfx/fx), after which RNA sequencing (RNA‐seq), qPCR, Western blot, immunofluorescence, and immunohistochemistry were used to investigate the impacts of AhR on periodontitis and its mechanism. Finally, we determined the therapeutic effect of AhR agonist 6‐Formylindolo[3,2‐b]carbazole (FICZ) administration on murine periodontitis and verified the effects of FICZ on macrophage polarization in vitro.ResultsAhR expression was enhanced in macrophages from periodontitis patients. Deletion of AhR from macrophages aggravated ligature‐induced periodontitis and promoted the inflammatory response. Calcium/calmodulin‐stimulated protein kinase II (CaMKII) phosphorylation was accelerated in AhR‐deficient macrophages. Inhibiting CaMKII phosphorylation ameliorated periodontitis in Lyz2‐Cre+/− AhRfx/fx mice. FICZ treatment blocked alveolar bone loss and relieved periodontal inflammation. FICZ diminished M1 macrophage polarization and promoted M2 macrophage polarization upon M1 macrophage induction.ConclusionAhR played a protective role in the pathogenesis of periodontitis by orchestrating macrophage polarization via interacting with the CaMKII signaling pathway.

中文翻译：

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除了转录之外，芳烃受体通过与 CaMKII 相互作用在牙周炎中发挥保护作用


背景芳烃受体（AhR）已被研究作为一种细胞内模式识别受体，可以识别细菌色素。为了确定牙周炎的潜在治疗靶点，我们研究了 AhR 在牙周炎中的表达及其在牙周炎发病机制中的作用。方法首先，我们分析了来自人类牙周组织的单细胞数据集中的 AhR 表达。使用定量聚合酶链反应（qPCR）、免疫荧光和免疫组织化学来验证AhR水平。后来，我们确定了骨髓特异性 AhR 缺陷小鼠（Lyz2-Cre）结扎诱导的牙周炎的表型+/-啊R外汇/外汇），然后利用RNA测序（RNA-seq）、qPCR、Western blot、免疫荧光和免疫组织化学研究AhR对牙周炎的影响及其机制。最后，我们确定了AhR激动剂6-甲酰吲哚并[3,2-b]咔唑（FICZ）对小鼠牙周炎的治疗效果，并验证了FICZ对体外巨噬细胞极化的影响。结果牙周炎患者巨噬细胞中AhR表达增强。巨噬细胞中 AhR 的缺失会加重结扎诱发的牙周炎并促进炎症反应。 AhR 缺陷型巨噬细胞中钙/钙调蛋白刺激的蛋白激酶 II (CaMKII) 磷酸化加速。抑制 CaMKII 磷酸化可改善 Lyz2-Cre 中的牙周炎+/-啊R外汇/外汇老鼠。 FICZ 治疗可阻止牙槽骨流失并缓解牙周炎症。 FICZ 在 M1 巨噬细胞诱导后减少了 M1 巨噬细胞极化并促进了 M2 巨噬细胞极化。结论AhR通过与CaMKII信号通路相互作用，协调巨噬细胞极化，在牙周炎的发病过程中发挥保护作用。