Activation of TLR7 increases CCND3 expression via the downregulation of miR-15b in B cells of systemic lupus erythematosus
Activation of TLR7 increases CCND3 expression via the downregulation of miR-15b in B cells of systemic lupus erythematosus
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TLR7 激活通过下调系统性红斑狼疮 B 细胞中 miR-15b 增加 CCND3 表达
DOI：
10.1038/cmi.2015.48
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发表时间：
2016-11-01
影响因子：
24.1
通讯作者：
Fan, Hongye
中科院分区：
文献类型：
--
作者：
Ren, Deshan;Liu, Fei;Fan, Hongye
系统性红斑狼疮 (SLE) 是一种以 B 细胞高反应性为特征的自身免疫性疾病。 SLE B 细胞中 Toll 样受体 7 (TLR7) 信号通路异常激活。 CyclinD3 (CCND3) 在 B 细胞增殖、发育和分化中发挥重要作用。尽管之前的研究重点关注TLR7对自发生发中心发育的B细胞内在作用，但TLR7对SLE B细胞中CCND3的影响仍不清楚。在这里，我们使用 B 细胞分析芯片，发现 CCND3 与 SLE 相关，并且在 SLE B 细胞中显着升高。此外，我们确定 SLE 患者和 B6 的 B 细胞中 CCND3 的表达水平较高，而 miR-15b 的表达水平显着较低。 MRL-Faslpr/J 狼疮小鼠与正常受试者相比。此外，我们证明 TLR7 的激活在体外 B 细胞中显着增加 CCND3 表达，但显着降低 miR-15b，并且我们确定 CCND3 是 miR-15b 的直接靶标。为了进一步证实我们的结果，我们根据先前描述的方案，通过用 TLR-7 激动剂咪喹莫特 (IMQ) 局部治疗 C57BL/6 (B6) 小鼠 8 周，建立了另一个狼疮模型。预计，局部使用 IMQ 治疗也会显着增加 B6 小鼠 B 细胞中的 CCND3 并减少 miR-15b。综上所述，我们的结果表明，TLR7 的激活通过下调 B 细胞中 miR-15b 来增加 CCND3 的表达。因此，这些发现表明外在因素诱导的CCND3表达可能导致SLE中B细胞的异常。
Systemic lupus erythematosus (SLE) is an autoimmune disease characterized by B-cell hyperreactivity. The Toll-like receptor 7 (TLR7) signaling pathway is abnormally activated in SLE B cells. CyclinD3 (CCND3) plays an important role in B-cell proliferation, development, and differentiation. Although previous studies focused on the B cell-intrinsic role of TLR7 for the development of spontaneous germinal centers, the influence of TLR7 on CCND3 in SLE B cells is still not clear. Here, we used a B-cell profiling chip and found that CCND3 was related to SLE and significantly elevated in SLE B cells. Moreover, we determined that the expression level of CCND3 was higher, while miR-15b was significantly lower in the B cells from SLE patients and B6. MRL-Faslpr/J lupus mice compared to normal subjects. Furthermore, we demonstrated that the activation of TLR7 dramatically increased CCND3 expression but significantly decreased miR-15b in B cells in vitro and we identified that CCND3 is a direct target of miR-15b. To further confirm our results, we established another lupus model by topically treating C57BL/6 (B6) mice with the TLR-7 agonist imiquimod (IMQ) for 8 weeks according to the previously described protocol. Expectedly, topical treatment with IMQ also significantly increased CCND3 and decreased miR-15b in B cells of B6 mice. Taken together, our results identified that the activation of TLR7 increased CCND3 expression via the downregulation of miR-15b in B cells; thus, these findings suggest that extrinsic factor-induced CCND3 expression may contribute to the abnormality of B cell in SLE.