Up-Regulation of TLR7-Mediated IFN-α Production by Plasmacytoid Dendritic Cells in Patients With Systemic Lupus Erythematosus.

Kei Sakata,Shingo Nakayamada,Kazuhisa Nakano,Akina Ishii,Yusuke Miyazaki,Satoshi Kubo,Yoshiya Tanaka

doi:10.3389/fimmu.2018.01957

Kei Sakata, Shingo Nakayamada + Show 5 more

Open Access

https://doi.org/10.3389/fimmu.2018.01957

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Abstract

Objectives: Aberrant and persistent production of interferon-α (IFN-α) by plasmacytoid dendritic cells (pDCs) is known to play a key role in the pathogenesis of systemic lupus erythematosus (SLE). To assess the precise function of pDCs in SLE patients, we investigated the differential regulation of Toll-like receptor 7 (TLR7) and TLR9 responses during IFN-α production by pDCs.Methods: Peripheral blood mononuclear cells (PBMCs) in SLE patients without hydroxychloroquine treatment, rheumatoid arthritis patients and heathy controls were stimulated with TLR7 and TLR9 agonists. To investigate the priming effect by cytokines, PBMCs from healthy controls were pre-treated with various cytokines and stimulated with TLR7 and TLR9 agonists. The IFN-α production in pDCs was detected by flow cytometry.Results: TLR7-mediated IFN-α production was up-regulated and correlated positively with disease activity in SLE. Conversely, TLR9-mediated IFN-α production was down-regulated. Differential regulation of TLR7/9 response in SLE was independent of TLR7 and TLR9 expression levels. Furthermore, in vitro experiments indicated that TLR7-mediated IFN-α production was up-regulated by pre-treatment with type I IFN, whereas TLR9-mediated IFN-α production was down-regulated by pre-treatment with type II IFN.Conclusions: Our study indicates the association between up-regulation of TLR7- mediated IFN-α production by pDCs and disease activity and that TLR7 and TLR9 responses were reversely regulated on pDCs in SLE patients. Thus, type I IFN and TLR7-mediated IFN-α production were involved in a vicious cycle, causing hyper production of IFN-α by pDCs during the pathogenic processes of SLE.

Highlights

Systemic lupus erythematosus (SLE) is a chronic autoimmune disease with multiple clinical manifestations that differ from one patient to another [1]
All were Asians, and the mean age of SLE was 42.0 years that was matched with healthy donors but not with rheumatoid arthritis (RA) patients
Co-localization of Toll-like receptor 7 (TLR7) with Rab7 and LAMP1, but not with EEA1 was increased by pre-treatment with IFN-α (Figure 6). These results demonstrate that increased TLR7 trafficking to lysosome-related organelle by type I IFN may cause the up-regulation of TLR7-mediated IFN-α production in plasmacytoid dendritic cells (pDCs), without affecting TLR7 expression levels

Summary

Introduction

Systemic lupus erythematosus (SLE) is a chronic autoimmune disease with multiple clinical manifestations that differ from one patient to another [1]. SLE is an extremely heterogeneous disease in all aspects, but recent studies have demonstrated characteristic induction of type I interferon-regulated genes (IFN-signature), which is linked to a more severe disease activity with organ failure, in patients with SLE [4,5,6]. Type I IFN is mainly produced by plasmacytoid dendritic cells (pDCs) when stimulated through Toll-like receptor 7 (TLR7) and TLR9. In SLE patients, abnormal stimulation of TLR7 and TLR9 by self-nucleic acids seems to contribute persistent production of type I IFN. Type I IFN production by pDCs upon TLR7/9 stimulation has been implicated as a key player in the pathogenesis of SLE. Targeting type I IFNs and TLR7/9 has recently become a major treatment strategy in SLE [7,8,9,10]

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