Manganese suppresses the development of oral leukoplakia by activating the immune response
Manganese suppresses the development of oral leukoplakia by activating the immune response
复制标题
锰通过激活免疫反应抑制口腔白斑的发展
DOI：
10.1111/odi.14412
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发表时间：
2022-11-21
期刊：
影响因子：
3.8
通讯作者：
Zeng，Xin
中科院分区：
文献类型：
--
作者：
Shi，Yujie;Su，Chongying;Zeng，Xin
目的锰离子(Mn2+)通过激活cGAS-STING途径促进抗肿瘤免疫应答，但目前尚不清楚Mn2+是否能阻止癌前病变的恶变。探讨Mn2+对口腔白斑(OLK)的治疗作用。方法采用电感耦合等离子体原子发射光谱仪(ICPAES)对口腔白斑患者外周血中的锰进行分析。采用树突状细胞(DC)/巨噬细胞、CD8+T细胞和发育不良口腔角质形成细胞(DOK)共培养模型，分析Mn2+在模拟OLK免疫微环境中的作用和机制。采用Western印迹、RT-PCR、流式细胞仪、酶联免疫吸附试验(ELISA法)和乳酸脱氢酶(LDH)法检测Mn2+在该模型中的作用机制。采用4-硝基喹啉氧化物(4NQO)诱导的OLK小鼠模型，研究了Mn2+对OLK进展的抑制作用，制备了一种新型的Mn2+鸟苷-单宁酸水凝胶(G-TA@Mn2+水凝胶)，并评价了其在治疗OLK中的优势。在共培养模型中，Mn2+促进DC和巨噬细胞的成熟和抗原提呈，增强CD8+T细胞的激活，从而有效地杀伤DOK。机制分析发现，Mn2+通过激活cGAS-STING途径增强抗OLK免疫应答。此外，Mn2+还抑制了4NQO诱发的小鼠癌变过程。此外，G-TA@Mn2+水凝胶具有较好的抗OLK作用。结论Mn2+通过激活cGAS-STING途径增强抗OLK免疫应答，是治疗OLK的一种潜在的新途径。
ObjectiveManganese ion (Mn2+) is reported to promote the antitumor immune response by activating the cGAS‐STING pathway, but it is unknown whether Mn2+can prevent the malignant transformation of precancerous lesions. The effects of Mn2+in treating oral leukoplakia (OLK) were explored in this work.MethodsPeripheral blood Mn analysis of the patients was performed using inductively coupled plasma atomic emission spectroscopy (ICP–AES). A coculture model of dendritic cells (DCs)/macrophages, CD8+T cells, and dysplastic oral keratinocytes (DOKs) was employed to analyze the role and mechanism of Mn2+in a simulated OLK immune microenvironment. Western blot, RT–PCR, flow cytometry, enzyme‐linked immunosorbent assay (ELISA), and lactate dehydrogenase (LDH) assays were adopted to detect the mechanism of Mn2+in this model. 4‐nitroquinoline oxide (4NQO)‐induced OLK mice were used to assess the role of Mn2+in suppressing OLK progression, and a novel Mn2+‐loaded guanosine‐tannic acid hydrogel (G‐TA@Mn2+hydrogel) was fabricated and evaluated for its advantages in OLK therapy.ResultsThe content of Mn in patients' peripheral blood was negatively related to the progression of OLK. Mn2+promoted the maturation and antigen presentation of DCs and macrophages and enhanced the activation of CD8+T cells in the coculture model, resulting in effective killing of DOKs. Mechanistic analysis found that Mn2+enhanced the anti‐OLK immune response by activating the cGAS‐STING pathway. Moreover, Mn2+suppressed the development of 4NQO–induced carcinogenesis in the mouse model. In addition, the G‐TA@Mn2+hydrogel had better anti‐OLK effects.ConclusionsMn2+enhanced the anti‐OLK immune response by activating the cGAS‐STING pathway, and the G‐TA@Mn2+hydrogel is a potential novel therapeutic approach for OLK treatment.