Dataset Information

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

ABSTRACT: Objectives: Aberrant and persistent production of interferon-? (IFN-?) 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-? 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-? production in pDCs was detected by flow cytometry. Results: TLR7-mediated IFN-? production was up-regulated and correlated positively with disease activity in SLE. Conversely, TLR9-mediated IFN-? 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-? production was up-regulated by pre-treatment with type I IFN, whereas TLR9-mediated IFN-? production was down-regulated by pre-treatment with type II IFN. Conclusions: Our study indicates the association between up-regulation of TLR7- mediated IFN-? 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-? production were involved in a vicious cycle, causing hyper production of IFN-? by pDCs during the pathogenic processes of SLE.

SUBMITTER: Sakata K

PROVIDER: S-EPMC6121190 | biostudies-literature | 2018

REPOSITORIES: biostudies-literature

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

Sakata Kei K Nakayamada Shingo S Miyazaki Yusuke Y Kubo Satoshi S Ishii Akina A Nakano Kazuhisa K Tanaka Yoshiya Y

Frontiers in immunology 20180828

<b>Objectives:</b> 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. <b>Methods:</b> Peripheral blood mononuclear cells (PBMCs) in SLE patients without hydroxychloroquine treatment, ...[more]

PMID: 30210502

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Project description:BackgroundIt is well known that interferon (IFN)-alpha is important to the pathogenesis of systemic lupus erythematosus (SLE). However, several reports have indicated that the number of IFN-alpha producing cells are decreased or that their function is defective in patients with SLE. We studied the function of plasmacytoid dendritic cells (pDCs) under persistent stimulation of Toll-like receptor (TLR)9 via a TLR9 ligand (CpG ODN2216) or SLE serum.MethodsThe concentrations of IFN-alpha were determined in serum and culture supernatant of peripheral blood mononuclear cells (PBMCs) from SLE patients and healthy controls after stimulation with CpG ODN2216 or SLE serum. The numbers of circulating pDCs were analyzed by fluoresence-activated cell sorting analysis. pDCs were treated with CpG ODN2216 and SLE serum repeatedly, and levels of produced IFN-alpha were measured. The expression of IFN-alpha signature genes and inhibitory molecules of TLR signaling were examined in PBMCs from SLE patients and healthy control individuals.ResultsAlthough there was no significant difference in serum concentration of IFN-alpha and number of circulating pDCs between SLE patients and healthy control individuals, the IFN-alpha producing capacity of PBMCs was significantly reduced in SLE patients. Interestingly, the degree which TLR9 ligand-induced IFN-alpha production in SLE PBMCs was inversely correlated with the SLE serum-induced production of IFN-alpha in healthy PMBCs. Because repeated stimulation pDCs with TLR9 ligands showed decreased level of IFN-alpha production, continuous TLR9 stimulation may lead to decreased production of IFN-alpha in SLE PBMCs. In addition, PBMCs isolated from SLE patients exhibited higher expression of IFN-alpha signature genes and inhibitory molecules of TLR signaling, indicating that these cells had already undergone IFN-alpha stimulation and had become desensitized to TLR signaling.ConclusionWe suggest that the persistent presence of endogenous IFN-alpha inducing factors induces TLR tolerance in pDCs of SLE patients, leading to impaired production of IFN-alpha.

Dataset Information

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

Publications

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

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