Ligation of CD180 inhibits IFN-α signaling in a Lyn-PI3K-BTK-dependent manner in B cells

• Published in: Cellular & molecular immunology 2017-02, Vol.14 (2), p.192-202
• Main Authors: You, Ming, Dong, Guanjun, Li, Fanlin, Ma, Feiya, Ren, Jing, Xu, Yujun, Yue, Huimin, Tang, Ruijing, Ren, Deshan, Hou, Yayi
• Format: Article
• Language: English
• Subjects: 1-Phosphatidylinositol 3-kinase; Animals; Antibodies; Antibody response; Antigens, CD - metabolism; Autoantibodies; B-Lymphocytes - metabolism; Biomedical and Life Sciences; Biomedicine; B细胞; CD18 antigen; Cell activation; Down-Regulation; Female; Gene Expression Regulation - drug effects; Humans; IFN-α; IFN-γ; Immunology; Interferon; Interferon-alpha - metabolism; Lupus; Lupus Erythematosus, Systemic - immunology; Lupus Erythematosus, Systemic - pathology; Lymphocytes B; Medical Microbiology; Mice, Inbred C57BL; Mice, Inbred MRL lpr; Microbiology; Phenotype; Phosphatidylinositol 3-Kinases - metabolism; Phosphorylation; Phosphotyrosine - metabolism; Plasma cells; Protein-Tyrosine Kinases - metabolism; research-article; Signal Transduction; Spleen - metabolism; Spleen - pathology; src-Family Kinases - metabolism; STAT2 Transcription Factor - metabolism; Systemic lupus erythematosus; Toll-Like Receptor 7 - metabolism; Toll-Like Receptor 9 - metabolism; Toll-like receptors; Toll样受体; Vaccine; α-Interferon; 信号转导; 系统性红斑狼疮; 结扎; 转录激活因子
• ISSN: 1672-7681; 2042-0226
• DOI: 10.1038/cmi.2015.61

A hallmark of systemic lupus erythematosus （SLE） is the consistent production of various auto-antibodies by auto-reactive B cells. Interferon-α（IFN-α） signaling is highly activated in SLE B cells and plays a vital role in the antibody response by B cells. Previous studies have shown that CD180-negative B cells, which are dramatically increased in SLE patients, are responsible for the production of auto-antibodies. However, the association between CD180 and IFN-αsignaling remains unknown. In the present study, we explored the effect of CD180 on regulating the activation of IFN-α signaling in B cells. We found that the number of CD180-negative B cells was increased in MRIJMp-Fas（Ipr/Ipr） lupus-prone mice compared with wild-type mice. Phenotypic analysis showed that CD180-negative B cells comprised CD138＋ plasmablast/plasma cells and GL-7＋ germinal center （GC） B cells. Notably, ligation of CD180 significantly inhibited the I FN-α-induced phosphorylation of signal transducer and activator of transcription 2 （STAT-2） and expression of IFN-stimulated genes （ISGs） in a Lyn-PI3K-BTK-dependent manner in vitro. Moreover, ligation of CD180 could also inhibit IFN-α-induced ISG expression in B cells in vivo. Furthermore, the Toll-like receptor 7 and Toll-like receptor 9 signaling pathways could significantly downregulate CD180 expression and modulate the inhibitory effect of CD180 signaling on the activation of I FN-a signaling. Collectively, our results highlight the close association between the increased proportion of CD180-negative B cells and the activation of IFN-α signaling in SLE. Our data provide molecular insight into the mechanism of IFN-α signaling activation in SLE B cells and a potential therapeutic approach for SLE treatment.