State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, Chinese Academy of Medical Sciences Research Unit of Oral Carcinogenesis and Management, West China Hospital of Stomatology, Sichuan University, Chengdu, China.
Front Immunol. 2022 Apr 14;13:838109. doi: 10.3389/fimmu.2022.838109. eCollection 2022.
Damaged and dead cells release cell-free DNA (cfDNA) that activates cyclic GMP-AMP (cGAMP) synthase (cGAS), which leads to the activation of stimulator of interferon genes (STING) the second messenger cGAMP. STING promotes the production of inflammatory cytokines and type I interferons to induce an inflammatory response. Oral lichen planus (OLP), a chronic autoimmune disease involving oral mucosa characterized by the apoptosis of keratinocytes mediated by T-lymphocytes, is related to the activation of multiple inflammatory signaling pathways. Currently, the relationship between cfDNA and OLP has not been confirmed. We hypothesized that cfDNA may be a potential therapeutic target for OLP.
cfDNA was extracted from the saliva and plasma of OLP patients; its concentration was measured using the Quanti-iT-PicoGree kit and its relationship with OLP inflammation was assessed. cfDNA of OLP patients (cfDNA-OLP) was transfected into THP-1 macrophages and the expression of inflammatory factors was investigated by performing quantitative real time PCR (qRT-PCR), western blotting, and enzyme-linked immunosorbent assay (ELISA). STING expression was analyzed in the tissues of OLP patients and healthy controls using immunohistochemical staining and western blotting. siRNA was used to knockdown expression in THP-1 macrophages, and the inflammatory cytokines tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6) secreted by cells following cfDNA-OLP transfection were detected using ELISA. Finally, the effect of the cationic polymer PAMAM-G3 was evaluated on the treatment of inflammation induced by cfDNA-OLP.
The concentration of cfDNA in the saliva and plasma of OLP patients was considerably higher than that of healthy controls, and it positively correlated with the levels of inflammatory cytokines and clinical characteristics. cfDNA-OLP induced an inflammatory response in THP-1 macrophages. STING expression was significantly higher in OLP tissues than in the gingival tissues of healthy controls. STING knockdown suppressed cfDNA-OLP-induced inflammation in THP-1 macrophages. PAMAM-G3 inhibited the inflammatory response caused by cfDNA-OLP.
The cfDNA level is increased in OLP patients, and the STING pathway activated by cfDNA-OLP might play a critical role in OLP pathogenesis. Treatment with PAMAM-G3 reduced the inflammation induced by cfDNA-OLP, and therefore, may be a potential treatment strategy for OLP.
受损和死亡的细胞释放无细胞 DNA（cfDNA），激活环鸟苷酸-腺苷酸（cGAMP）合酶（cGAS），导致干扰素基因刺激物（STING）第二信使 cGAMP 的激活。STING 促进炎性细胞因子和 I 型干扰素的产生，以诱导炎症反应。口腔扁平苔藓（OLP）是一种涉及口腔黏膜的慢性自身免疫性疾病，其特征是 T 淋巴细胞介导的角质形成细胞凋亡，与多种炎症信号通路的激活有关。目前，cfDNA 与 OLP 之间的关系尚未得到证实。我们假设 cfDNA 可能是 OLP 的一个潜在治疗靶点。
从 OLP 患者的唾液和血浆中提取 cfDNA；使用 Quanti-iT-PicoGree 试剂盒测量其浓度，并评估其与 OLP 炎症的关系。将 OLP 患者的 cfDNA（cfDNA-OLP）转染到 THP-1 巨噬细胞中，通过实时定量 PCR（qRT-PCR）、Western blot 和酶联免疫吸附试验（ELISA）检测炎症因子的表达。使用免疫组织化学染色和 Western blot 分析 OLP 患者和健康对照组织中的 STING 表达。使用 siRNA 敲低 THP-1 巨噬细胞中的表达，并通过 ELISA 检测 cfDNA-OLP 转染后细胞分泌的肿瘤坏死因子-α（TNF-α）和白细胞介素-6（IL-6）等炎性细胞因子。最后，评估阳离子聚合物 PAMAM-G3 对 cfDNA-OLP 诱导的炎症的治疗作用。
OLP 患者唾液和血浆中的 cfDNA 浓度明显高于健康对照组，且与炎症细胞因子水平和临床特征呈正相关。cfDNA-OLP 诱导 THP-1 巨噬细胞发生炎症反应。与健康对照组的牙龈组织相比，OLP 组织中 STING 的表达显著升高。STING 敲低抑制了 THP-1 巨噬细胞中 cfDNA-OLP 诱导的炎症反应。PAMAM-G3 抑制了 cfDNA-OLP 引起的炎症反应。
OLP 患者 cfDNA 水平升高，cfDNA-OLP 激活的 STING 途径可能在 OLP 发病机制中起关键作用。用 PAMAM-G3 治疗可减轻 cfDNA-OLP 诱导的炎症，因此可能是 OLP 的一种潜在治疗策略。
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