title: Activation of TLR7 increases CCND3 expression via the downregulation of miR-15b in B cells of systemic lupus erythematosus.
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.
authors.affiliation: The State Key Laboratory of Pharmaceutical Biotechnology, Division of Immunology, Medical School, Nanjing University, Nanjing 210093, People's Republic of China.
authors.forename: Deshan
authors.initials: D
authors.lastname: Ren
authors.affiliation: The State Key Laboratory of Pharmaceutical Biotechnology, Division of Immunology, Medical School, Nanjing University, Nanjing 210093, People's Republic of China.
authors.forename: Fei
authors.initials: F
authors.lastname: Liu
authors.affiliation: The State Key Laboratory of Pharmaceutical Biotechnology, Division of Immunology, Medical School, Nanjing University, Nanjing 210093, People's Republic of China.
authors.forename: Guanjun
authors.initials: G
authors.lastname: Dong
authors.affiliation: The State Key Laboratory of Pharmaceutical Biotechnology, Division of Immunology, Medical School, Nanjing University, Nanjing 210093, People's Republic of China.
authors.forename: Ming
authors.initials: M
authors.lastname: You
authors.affiliation: The State Key Laboratory of Pharmaceutical Biotechnology, Division of Immunology, Medical School, Nanjing University, Nanjing 210093, People's Republic of China.
authors.forename: Jianjian
authors.initials: J
authors.lastname: Ji
authors.affiliation: The State Key Laboratory of Pharmaceutical Biotechnology, Division of Immunology, Medical School, Nanjing University, Nanjing 210093, People's Republic of China.
authors.forename: Yahong
authors.initials: Y
authors.lastname: Huang
authors.affiliation: The State Key Laboratory of Pharmaceutical Biotechnology, Division of Immunology, Medical School, Nanjing University, Nanjing 210093, People's Republic of China.|Jiangsu Key Laboratory of Molecular Medicine, Nanjing 210093, People's Republic of China.
authors.forename: Yayi
authors.initials: Y
authors.lastname: Hou
authors.affiliation: School of Life Science and Technology, China Pharmaceutical University, Nanjing 210009, Jiangsu, People's Republic of China.
authors.forename: Hongye
authors.initials: H
authors.lastname: Fan
mesh_terms: D000328:Adult; D000634:Aminoquinolines; D000818:Animals; D018941:Antigens, CD19 / Q000378:metabolism; D001402:B-Lymphocytes / Q000378:metabolism*; D016000:Cluster Analysis; D056743:Cyclin D3 / Q000235:genetics* / Q000378:metabolism; D004195:Disease Models, Animal; D015536:Down-Regulation / Q000235:genetics*; D005260:Female; D020869:Gene Expression Profiling; D063990:Gene Ontology; D053263:Gene Regulatory Networks; D006801:Humans; D000077271:Imiquimod; D008180:Lupus Erythematosus, Systemic / Q000235:genetics* / Q000276:immunology / Q000473:pathology; D008810:Mice, Inbred C57BL; D035683:MicroRNAs / Q000235:genetics* / Q000378:metabolism; D060066:Protein Interaction Maps; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D051199:Toll-Like Receptor 7 / Q000378:metabolism*; D015854:Up-Regulation / Q000235:genetics
chemical_list: D000634:Aminoquinolines; D018941:Antigens, CD19; C534696:CCND3 protein, human; C534697:Ccnd3 protein, mouse; D056743:Cyclin D3; C505361:MIRN15 microRNA, human; D035683:MicroRNAs; C570833:Mirn15 microRNA, mouse; D012333:RNA, Messenger; D051199:Toll-Like Receptor 7; D000077271:Imiquimod