Background Characteristic induction of interferon (IFN) signature is known to play a pivotal role in patients with SLE and plasmacytoid dendritic cells (pDC) are major source of Type I IFN. However, mechanisms of Type I IFN production from pDC in the pathogenesis of SLE remain unclear.
Objectives To elucidate the function of pDC in SLE, we shed light upon Toll-like receptor (TLR) 7 and TLR9-mediated signaling during Type I IFN production from pDC in patients with SLE or healthy controls (HC).
Methods Peripheral blood mononuclear cells (PBMCs) in 68 SLE patients without hydroxychloroquin treatment, 37 RA patients and 24 HC were analyzed in the presence of a TLR7 agonist loxoribine and a TLR9 agonist CpG 2216. The IFN-α production in Lin-HLA-DR+CD123+CD11c- pDCs was detected by flow cytometry.
Results The spontaneous production of IFN-α in pDCs was marginal, but the TLR7 agonist markedly up-regulated IFN-α production from pDCs in SLE patients compared to that in HC. Such an up-regulation of IFN-α was not observed in pDCs in RA. On the other hands, TLR9-mediated IFN-α production from pDCs in SLE was down-regulated compared to that in HC. Furthermore, TLR7- and TLR9-mediated IFN-α production from pDCs in SLE patients were positively and negatively correlated with SLEDAI and dsDNA-ab titers, respectively. The expression of TLR7 and TLR9 on pDCs was comparable among SLE, RA and HC, indicating that the difference of TLR response was not depend on alterations of TLR expression levels. By in vitro experiments under pre-treatment with multiple cytokines, both Type I and Type II IFN up-regulated the TLR7-mediated IFN-α production from pDCs, but they down-regulated the TLR9-mediated IFN-α production, suggesting that up-regulation of TLR7 responses and down-regulation of TLR9 responses of pDCs in SLE patients were regulated by Type I and Type II IFNs.
Conclusions This is the first report demonstrated the differential regulation of TLR7 and TLR9 by type I IFN in pDCs in SLE patients, namely, TLR7 and TLR9 response were regulated by Type I and Type II IFNs. Taken together, TLR7-mediated pDC response plays a pivotal role in the increase in IFN-signature in SLE patients and could be a potential therapeutic target for SLE.
Disclosure of Interest K. Sakata Employee of: Mitsubishi Tanabe Pharma Corporation, S. Nakayamada: None declared, Y. Miyazaki: None declared, S. Kubo: None declared, K. Nakano: None declared, Y. Tanaka Grant/research support from: Mitsubishi-Tanabe, Takeda, Chugai, Astellas, Eisai, Taisho-Toyama, Kyowa-Kirin, Abbvie, Bristol-Myers., Consultant for: Abbvie, Daiichi-Sankyo, Chugai, Takeda, Mitsubishi-Tanabe, Bristol-Myers, Astellas, Eisai, Janssen, Pfizer, Asahi-kasei, Eli Lilly, GlaxoSmithKline, UCB, Teijin, MSD, Santen