Ligation of CD180 inhibits IFN-α signaling in a Lyn-PI3K-BTK-dependent manner in B cells.
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-α signaling 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 MRL/Mp-Fas(lpr/lpr) 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 IFN-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 IFN-α 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.
The State Key Laboratory of Pharmaceutical Biotechnology, Division of Immunology, Medical School, Nanjing University, Nanjing 210093, People's Republic of China.
Ming
M
You
The State Key Laboratory of Pharmaceutical Biotechnology, Division of Immunology, Medical School, Nanjing University, Nanjing 210093, People's Republic of China.
Guanjun
G
Dong
The State Key Laboratory of Pharmaceutical Biotechnology, Division of Immunology, Medical School, Nanjing University, Nanjing 210093, People's Republic of China.
Fanlin
F
Li
The State Key Laboratory of Pharmaceutical Biotechnology, Division of Immunology, Medical School, Nanjing University, Nanjing 210093, People's Republic of China.
Feiya
F
Ma
The State Key Laboratory of Pharmaceutical Biotechnology, Division of Immunology, Medical School, Nanjing University, Nanjing 210093, People's Republic of China.
Jing
J
Ren
The State Key Laboratory of Pharmaceutical Biotechnology, Division of Immunology, Medical School, Nanjing University, Nanjing 210093, People's Republic of China.
Yujun
Y
Xu
The State Key Laboratory of Pharmaceutical Biotechnology, Division of Immunology, Medical School, Nanjing University, Nanjing 210093, People's Republic of China.
Huimin
H
Yue
The State Key Laboratory of Pharmaceutical Biotechnology, Division of Immunology, Medical School, Nanjing University, Nanjing 210093, People's Republic of China.
Ruijing
R
Tang
The State Key Laboratory of Pharmaceutical Biotechnology, Division of Immunology, Medical School, Nanjing University, Nanjing 210093, People's Republic of China.
Deshan
D
Ren
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, Medical School, Nanjing University Nanjing 210093, People's Republic of China.
Yayi
Y
Hou
D000077329:Agammaglobulinaemia Tyrosine Kinase; D000818:Animals; D015703:Antigens, CD / Q000378:metabolism*; D001402:B-Lymphocytes / Q000378:metabolism*; D015536:Down-Regulation; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D016898:Interferon-alpha / Q000378:metabolism*; D008180:Lupus Erythematosus, Systemic / Q000276:immunology / Q000473:pathology; D008810:Mice, Inbred C57BL; D019463:Mice, Inbred MRL lpr; D010641:Phenotype; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D019000:Phosphotyrosine / Q000378:metabolism; D011505:Protein-Tyrosine Kinases / Q000378:metabolism*; D050795:STAT2 Transcription Factor / Q000378:metabolism; D015398:Signal Transduction; D013154:Spleen / Q000378:metabolism / Q000473:pathology; D051199:Toll-Like Receptor 7 / Q000378:metabolism; D051217:Toll-Like Receptor 9 / Q000378:metabolism; D019061:src-Family Kinases / Q000378:metabolism*
D015703:Antigens, CD; C092722:CD180 protein, human; D016898:Interferon-alpha; C490500:Ly78 protein, mouse; D050795:STAT2 Transcription Factor; D051199:Toll-Like Receptor 7; D051217:Toll-Like Receptor 9; D019000:Phosphotyrosine; D019869:Phosphatidylinositol 3-Kinases; D011505:Protein-Tyrosine Kinases; D000077329:Agammaglobulinaemia Tyrosine Kinase; C000625949:BTK protein, human; C060902:lyn protein-tyrosine kinase; D019061:src-Family Kinases