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Activation of TLR7 increases CCND3 expression via the downregulation of miR-15b in B cells of systemic lupus erythematosus

Cellular & Molecular Immunology volume 13, pages 764–775 (2016)Cite this article

Abstract

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.

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Acknowledgements

This work was supported by grants from the National Natural Science Foundation of China (Project number: 31370899) and the Fundamental Research Funds for the Central Universities (Project number: 2015PY007).

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Authors and Affiliations

  1. Division of Immunology, The State Key Laboratory of Pharmaceutical Biotechnology, Medical School, Nanjing University, Nanjing, 210093, People's Republic of China

    Deshan Ren, Fei Liu, Guanjun Dong, Ming You, Jianjian Ji, Yahong Huang & Yayi Hou

  2. School of Life Science and Technology, China Pharmaceutical University, Nanjing, 210009, Jiangsu, People's Republic of China

    Hongye Fan

  3. Jiangsu Key Laboratory of Molecular Medicine, Nanjing, 210093, People's Republic of China

    Yayi Hou

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  1. Deshan Ren
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Correspondence to Yayi Hou or Hongye Fan.

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Supplementary Information accompanies the paper on Cellular & Molecular Immunology's website (http://www.nature.com/cmi).

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Ren, D., Liu, F., Dong, G. et al. Activation of TLR7 increases CCND3 expression via the downregulation of miR-15b in B cells of systemic lupus erythematosus. Cell Mol Immunol 13, 764–775 (2016). https://doi.org/10.1038/cmi.2015.48

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