Administration of a microRNA-21 inhibitor improves the lupus-like phenotype in MRL/lpr mice by repressing Tfh cell-mediated autoimmune responses
Administration of a microRNA-21 inhibitor improves the lupus-like phenotype in MRL/lpr mice by repressing Tfh cell-mediated autoimmune responses
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给予 microRNA-21 抑制剂可通过抑制 Tfh 细胞介导的自身免疫反应来改善 MRL/lpr 小鼠的狼疮样表型
DOI：
10.1016/j.intimp.2022.108578
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发表时间：
2022-02-03
影响因子：
5.6
通讯作者：
Zhao, Ming
中科院分区：
文献类型：
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作者：
Gao, Xiaofei;Song, Yang;Zhao, Ming
背景：抑制Tfh细胞过度扩增可预防系统性红斑狼疮（SLE）的自身免疫反应和疾病发作。miR-21在SLE CD 4（+）T细胞中高度表达，但抑制miR-21是否可以减少Tfh细胞扩增并缓解狼疮的疾病进展尚不清楚。目的：探讨miR-21在调节Tfh细胞增殖中的作用及其分子机制，并探讨其对SLE的治疗作用。方法：我们用Antagomir-21处理12周龄的MRL/lpr小鼠，其在体内特异性抑制miR-21。治疗12周后，我们检测了Tfh细胞和生发中心（GC）B细胞的比例以及血清自身抗体水平，并通过组织学评分和蛋白尿来评估疾病的严重程度。我们通过PGSK探针测定了CD 4 + T细胞中细胞内游离铁的水平，并通过qPCR检测了Fth和Tfrc基因的表达。免疫组化（IHC）用于评估引流淋巴结（dLN）和脾脏中的5-hmC水平。结果和结论：抑制miR-21显著降低了Tfh细胞和GC B细胞的扩增。此外，Antagomir-21高度改善了MRL/lpr小鼠的皮肤病变和肾炎。抑制miR-21可减少T细胞内铁积累和DNA羟甲基化。总之，体内抑制miR-21可改善细胞内铁稳态并抑制Tfh细胞过度扩增，有助于降低小鼠狼疮的自身免疫反应和缓解疾病症状。
Background: Inhibiting Tfh cell overexpansion prevents autoimmune responses and disease flares in systemic lupus erythematosus (SLE). miR-21 is highly expressed in SLE CD4(+) T cells, but whether inhibiting miR-21 can reduce Tfh cell expansion and alleviate the disease progression of lupus is unclear. Aim of the study: To address the role and molecular mechanism of miR-21 in regulating Tfh cell expansion and its therapeutic effect on SLE. Methods: We treated 12-week-old MRL/lpr mice with Antagomir-21, which specifically inhibited miR-21 in vivo. After 12 weeks of treatment, we examined the proportions of Tfh cells and germinal center (GC) B cells and serum levels of autoantibodies and evaluated disease severity by histological scoring and albuminuria. We determined the level of intracellular free iron in CD4+ T cells by PGSK probe and examined the expression of the Fth and Tfrc genes by qPCR. Immunohistochemistry (IHC) was used to assess the 5-hmC level in the draining lymph nodes (dLNs) and spleen. Results and Conclusions: Inhibiting miR-21 significantly reduced the expansion of Tfh cells and GC B cells. Furthermore, Antagomir-21 highly improved skin lesions and nephritis in MRL/lpr mice. Inhibiting miR-21 reduced intracellular iron accumulation and DNA hydroxymethylation in T cells. In conclusion, inhibiting miR-21 in vivo improves intracellular iron homeostasis and inhibits Tfh cell overexpansion, contributing to reduced autoimmune responses and the remission of disease symptoms in murine lupus.