BackgroundInterferon-α (IFN-α) is increased and plays an important role in the pathogenesis of systemic lupus erythematosus (SLE). Plasmacytoid dendritic cells (pDCs) are the main producer of IFN-α, but their IFN-α producing capacity has been shown to be unchanged or reduced when stimulated with a Toll-like receptor 9 (TLR9) agonist in patients with SLE compared to in healthy individuals. In this study, we investigated the IFN-α-producing capacity of lupus pDCs under different stimulation.MethodspDCs from patients with SLE and healthy controls (HC) were stimulated with TLR9 or TLR7 agonist, and their IFN-α producing capacity was examined by intracellular cytokine staining and flow cytometry. The correlation of IFN-α-producing capacity with serum IFN-α levels and disease activity was assessed. The effect of in vitro IFN-α exposure on IFN-α production by pDCs was examined. Localization of TLR7 in cellular compartments in pDCs was investigated.ResultsThe IFN-α producing capacity of pDCs was reduced after TLR9 stimulation, but increased when stimulated with a TLR7 agonist in SLE compared to in HC. IFN-α production by pDCs upon TLR9 stimulation was reduced and the percentage of IFN-α+pDC was inversely correlated with disease activity and serum IFN-α levels. However, the TLR7 agonist-induced IFN-α producing capacity of lupus pDCs was enhanced and correlated with disease activity and serum IFN-α. Exposure to IFN-α enhanced IFN-α production of TLR7-stimulated pDCs, but reduced that of pDCs activated with a TLR9 agonist. TLR7 localization was increased in late endosome/lysosome compartments in pDCs from SLE patients.ConclusionsThese findings indicate that enhanced TLR7 responses of lupus pDCs, owing to TLR7 retention in late endosome/lysosome and exposure to IFN-α, are associated with the pathogenesis of SLE.Electronic supplementary materialThe online version of this article (doi:10.1186/s13075-017-1441-7) contains supplementary material, which is available to authorized users.
BackgroundType I interferon (IFN) appears to contribute to the development of systemic lupus erythematosus (SLE). IFN-α production is known to be increased in peripheral blood mononuclear cells (PBMCs) from SLE patients. Although plasmacytoid dendritic cells (pDCs) is a major source of IFN-α, previous reports showed that IFN-α production by pDCs stimulated with a TLR-9 agonist was decreased in SLE compared to healthy controls (HC).ObjectivesWe set out to investigate an other endosomal TLR-signaling pathway in SLE by using TLR-7 agonist stimulation.MethodsBlood samples were obtained from 55 HC and 73 SLE patients, diagnosed according to the systemic lupus international collaborating clinics classification criteria for systemic lupus erythematosus (2012). PBMC from SLE patients and HC were stimulated with a TLR-9 agonist, CpG-A oligodeoxynucleotides (CpG-A ODN)-2216, and a TLR-7 agonist, imiquimod. The proportion of pDCs producing IFN-α was investigated by intracellular cytokine staining and flowcytometory. PBMC were pretreated with IFN-α for 24 hours, and then IFN-α production by pDCs was assessed after imiquimod stimulation.ResultsAs previously reported, the level of IFN-α production by pDCs stimulated with CpG-A ODN was reduced in SLE compared with HC. However, the proportion of IFN-α producing pDCs stimulated with imiquimod was significantly increased in SLE patients. The percentage of IFN-α producing pDCs stimulated with imiquimod was positively correlated with SLE disease activity index (SLEDAI) score, and that of pDCs stimulated with CpG-A ODN was negatively correlated with SLEDAI. The expression of TLR-7 on pDCs, but not TLR-9, was upregulated in SLE patients compared with HC. Furthermore, pretreatment with IFN-α increased IFN-α production by pDCs upon imiquimod stimulation.ConclusionsIFN-α production by pDCs form SLE patients was increased when stimulated with a TLR-7 agonist, and this was accompanied with upregulated TLR-7 expression in these cells. In murine lupus-models, TLR7-deletion has been shown to reduce autoimmune disease. The enhanced TLR-7 signaling pathway in pDC may play an important role in lupus pathology.References Christensen SR, et al. Toll-like receptor 7 and TLR9 dictate autoantibody specificity and have opposing inflammatory and regulatory roles in a murine model of lupus. Immunity. 2006; 25: 417–28.Sacre K, et al. Hydroxychloroquine is associated with impaired interferon-alpha and tumor necrosis factor-alpha production by plasmacytoid dendritic cells in systemic lupus erythematosus. Arthritis Res Ther. 2012;R155.Fukui R, et al. Unc93B1 restricts systemic lethal inflammation by orchestrating Toll-like receptor 7 and 9 trafficking. Immunity 2011; 35: 69–81. Disclosure of InterestNone declared
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