Tao Bei, Xiang Wei, Li Xianglong, He Chengsong, Chen Ligang, Xia Xiangguo, Peng Tangming, Peng Lilei, Yang Xiaobo, Zhong Chuanhong
Department of Rheumatology and Immunology, The Affiliated Hospital of Southwest Medical University, Luzhou, 646000, People's Republic of China.
Department of Neurosurgery, The Affiliated Hospital of Southwest Medical University, No. 25, Taiping Street, Luzhou, 646000, Sichuan Province, People's Republic of China.
Inflamm Res. 2021 Mar;70(3):285-296. doi: 10.1007/s00011-020-01433-y. Epub 2021 Jan 28.
microRNAs (miRNAs) play critical roles in embryogenesis, cell differentiation and the pathogenesis of several human diseases, including systemic lupus erythematosus (SLE). Toll-like receptors (TLRs) are also known to exert crucial functions in the immune response activation occurring in the pathogenesis of autoimmune diseases like SLE. Herein, the current study aimed to explore the potential role of miR-152-3p in TLR-mediated inflammatory response in SLE.
We determined the miR-152-3p expression profiles in CD4 T cells and peripheral blood mononuclear cells (PBMCs) harvested from patients with SLE and healthy controls, and analyzed the correlation between miR-152-3p expression and clinicopathological parameters. CD70 and CD40L expression patterns in CD4 T cells were assessed by RT-qPCR and flow cytometry. ChIP was adopted to determine the enrichment of DNA methyltransferase 1 (DNMT1) in the promoter region of myeloid differentiation factor 88 (MyD88).
The obtained findings revealed that miR-152-3p was highly-expressed in CD4 T cells and PBMCs of patients with SLE, and this high expression was associated with facial erythema, joint pain, double-stranded DNA, and IgG antibody. DNMT1 could be enriched in the MyD88 promoter, and miR-152-3p inhibited the methylation of MyD88 by targeting DNMT1. We also found that silencing miR-152-3p inhibited MyD88 expression not only to repress the autoreactivity of CD4 T cells and but also to restrain their cellular inflammation, which were also validated in vivo.
Our study suggests that miR-152-3p promotes TLR-mediated inflammatory response in CD4 T cells by regulating the DNMT1/MyD88 signaling pathway, which highlights novel anti-inflammatory target for SLE treatment.
微小RNA（miRNA）在胚胎发育、细胞分化以及包括系统性红斑狼疮（SLE）在内的多种人类疾病的发病机制中发挥着关键作用。Toll样受体（TLR）在SLE等自身免疫性疾病发病机制中发生的免疫反应激活过程中也发挥着关键作用。在本研究中，旨在探讨miR-152-3p在SLE中TLR介导的炎症反应中的潜在作用。
我们测定了从SLE患者和健康对照者采集的CD4 T细胞和外周血单个核细胞（PBMC）中miR-152-3p的表达谱，并分析了miR-152-3p表达与临床病理参数之间的相关性。通过RT-qPCR和流式细胞术评估CD4 T细胞中CD70和CD40L的表达模式。采用染色质免疫沉淀法（ChIP）确定DNA甲基转移酶1（DNMT1）在髓样分化因子88（MyD88）启动子区域的富集情况。
研究结果显示，miR-152-3p在SLE患者的CD4 T细胞和PBMC中高表达，且这种高表达与面部红斑、关节疼痛、双链DNA和IgG抗体相关。DNMT1可富集于MyD88启动子，miR-152-3p通过靶向DNMT1抑制MyD88的甲基化。我们还发现，沉默miR-152-3p不仅抑制MyD88表达以抑制CD4 T细胞的自身反应性，还抑制其细胞炎症，这在体内也得到了验证。
我们的研究表明，miR-152-3p通过调节DNMT1/MyD88信号通路促进CD4 T细胞中TLR介导的炎症反应，这为SLE治疗突出了新的抗炎靶点。
