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

Abstract

A hallmark of systemic lupus erythematosus (SLE) is the consistent production of various auto-antibodies by auto-reactive B cells. Interferon-a (IFN-a) 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-a signaling remains unknown. In the present study, we explored the effect of CD180 on regulating the activation of IFN-a 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 1 plasmablast/plasma cells and GL-7 1 germinal center (GC) B cells. Notably, ligation of CD180 significantly inhibited the IFN-a-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-a-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-a signaling. Collectively, our results highlight the close association between the increased proportion of CD180-negative B cells and the activation of IFN-a signaling in SLE. Our data provide molecular insight into the mechanism of IFN-a signaling activation in SLE B cells and a potential therapeutic approach for SLE treatment. Cellular & Molecular Immunology

Toll-Like Receptor Mediated Activation of Natural Autoantibody Producing B Cell Subpopulations in an Autoimmune Disease Model

“…Interestingly, we also found that anti-CD180 stimulation downregulated the mRNA expression of CD180, strengthening the possibility of autoregulation of CD180 expression by B cells. Signaling via TLRs can interfere with CD180 signals, since ligands of TLR7 and TLR9 have already been shown to downregulate CD180 expression in human peripheral blood B cells [16]. Nevertheless, according to our results, co-treatment with anti-CD180 and CpG reduced the expression of CD180 to a similar level as anti-CD180 did on its own, while CpG treatment alone had no significant effect on the expression of CD180.…”

“…The CD180-negative B cells were described as highly activated cells in SLE [11], and stimulation via CD180 is known to activate B cells [6]. Furthermore, TLR ligands were reported to downregulate the mRNA expression of CD180 molecule [16], thus we hypothesized that the decreased CD180 expression of dcSSc B cells could be a result of activation through TLRs. To investigate whether TLR stimulation leads to diminished expression of CD180 molecules in B cells, we stimulated tonsillar B cells with anti-CD180 antibody.…”

CD180 Ligation Inhibits TLR7- and TLR9-Mediated Activation of Macrophages and Dendritic Cells Through the Lyn-SHP-1/2 Axis in Murine Lupus

“…Our previous study and others have reported that the percentage of CD180-negative B cells is dramatically increased in PBMCs from SLE patients ( 32 , 33 ). However, the mode of CD180 expression on monocytes and DCs in SLE patients is still unknown.…”

“…Our previous study and others have reported that ligation of CD180 can activate Lyn and subsequently induce the activation of downstream signaling pathways ( 28 , 32 ). To gain mechanistic insight into how CD180 ligation leads to the phosphorylation of SHP-1 and SHP-2, we next investigated whether CD180 induced the phosphorylation of SHP-1 and SHP-2 through Lyn.…”

“…CD180 can influence the development, homeostasis and survival of immune cells, including macrophages, DCs and B cells, through phosphorylating various kinases, such as Lyn ( 27 – 31 ). Accumulating evidence has shown that CD180 is tightly associated with the pathogenesis of autoimmune diseases: CD180 can modulate the functions of antigen-presenting cells and regulate the development of collagen-induced arthritis; the population of CD180-negative B cell significantly increases in SLE patients and it changes in parallel with SLE disease activity ( 32 , 33 ). Notably, a close relationship exists between CD180 and the activation of TLRs pathways already.…”