Background and aims Aberrant and persistent production of type I interferon (IFN) is known to play a pivotal role in the pathogenesis of systemic lupus erythematosus (SLE), and plasmacytoid dendritic cells (pDCs) are the major source of type I IFN upon toll-like receptor 7 (TLR7) and TLR9 stimulation. However the respective impacts of TLR7 and TLR9 responses on type I IFN production in SLE has not been addressed.To investigate the precise function of pDCs in SLE patients, we shed light upon the differential regulation of TLR7/9 responses during type I IFN production from pDCs.
Methods PBMCs from SLE patients and healthy controls were analysed in the presence of a TLR7 agonist loxoribine and a TLR9 agonist CpG2216. The IFN-α production in Lin-HLA-DR+CD123+CD11c- pDCs was detected by flow cytometry.
Results We demonstrated that TLR7-mediated IFN-α production were up-regulated and were positively correlated with disease activity, conversely, TLR9-mediated IFN-α production were down-regulated in SLE. The differential regulation of TLR7/9 responses of pDCs was not dependent on expression levels of TLR7/9. Furthermore, in vitro experiments revealed that up-regulation of TLR7 response was caused by pre-treatment with type I IFNs, conversely, down-regulation of TLR9 response was caused by pre-treatment with type II IFN.
Conclusions This is the first report demonstrated the differential regulation of TLR7- and TLR9- mediated IFN-α production from pDCs in SLE, namely, caused by priming effects of type I and type II IFNs. Taken together, TLR7-, but not TLR9-, mediated IFN-α production contributes the pathogenesis of SLE, and TLR7 could be a potential therapeutic target for SLE.
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