Abstract
Activation of TLR7 and TLR9 by endogenous RNA- or DNA-containing ligands, respectively, can lead to hyper-activation of immune cells, including macrophages and DCs, subsequently contributes to the pathogenesis of SLE. CD180, a TLR-like protein, is specifically involved in the development and activation of immune cells. Our previous study and others have reported that CD180-negative B cells are dramatically increased in SLE patients and responsible for the production of auto-antibodies. However, the mode of CD180 expression on macrophages and DCs in SLE remains unclear and the role of CD180 on regulating TLR7- and TLR9-mediated activation of macrophages and DCs are largely unknown. In the present study, we found that the percentages of CD180-negative macrophages and DCs were both increased in SLE patients and lupus-prone MRL/lpr mice compared with healthy donors and wild-type mice, respectively. Notably, ligation of CD180 significantly inhibited the activation of TLR7 and TLR9 signaling pathways in macrophages and DCs through the Lyn-SHP-1/2 axis. What's more, injection of anti-CD180 Ab could markedly ameliorate the lupus-symptoms of imiquimod-treated mice and lupus-prone MRL/lpr mice through inhibiting the activation of macrophages and DCs. Collectively, our results highlight a critical role of CD180 in regulating TLR7- and TLR9-mediated activation of macrophages and DCs, hinting that CD180 can be regarded as a potential therapeutic target for SLE treatment.
Highlights
Systemic lupus erythematosus (SLE) is an autoimmune disease characterized by a loss of immunologic tolerance and hyper-activation of immune cells, which lead to aberrant production of pro-inflammatory cytokines, generation of antinuclear antibodies and multi-organ damage [1]
We found that the percentages of CD180-negative macrophages and dendritic cells (DCs) were both increased in SLE patients and lupus-prone MRL/lpr mice compared with healthy donors and wild-type mice, respectively
We investigated the role of CD180 in regulating the activation of macrophages and DCs induced by ligands of TLR7 and TLR9
Summary
Systemic lupus erythematosus (SLE) is an autoimmune disease characterized by a loss of immunologic tolerance and hyper-activation of immune cells, which lead to aberrant production of pro-inflammatory cytokines, generation of antinuclear antibodies and multi-organ damage [1]. CD180 Inhibits TLR7/9 Pathways Activations of macrophages and DCs have been shown to contribute to the pathogenesis of SLE: inappropriate or dysfunctional antigen presentation by DCs might promote the breakdown of immunologic tolerance in SLE [5,6,7]; monocytes/macrophages can infiltrate in target organ and contribute to SLE pathogenesis through the pro-inflammatory cytokines production [8,9,10]. Abnormal regulations of TLR7 and TLR9 pathways are critically involved in the activation of macrophages and DCs, subsequently break self-tolerance and contribute to the pathogenesis of SLE through antigen presentation and cytokines production, such as interferons, tumor necrosis factors (TNFs) and specific interleukins [18,19,20]. The identification of the negative regulators and details of the mechanisms by which TLR7 and TLR9 pathways are tightly controlled remain to be fully elucidated
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