Enhanced IFN-? production is associated with increased TLR7 retention in the lysosomes of palasmacytoid dendritic cells in systemic lupus erythematosus.
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ABSTRACT: Interferon-? (IFN-?) 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-?, but their IFN-? 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-?-producing capacity of lupus pDCs under different stimulation.pDCs from patients with SLE and healthy controls (HC) were stimulated with TLR9 or TLR7 agonist, and their IFN-? producing capacity was examined by intracellular cytokine staining and flow cytometry. The correlation of IFN-?-producing capacity with serum IFN-? levels and disease activity was assessed. The effect of in vitro IFN-? exposure on IFN-? production by pDCs was examined. Localization of TLR7 in cellular compartments in pDCs was investigated.The IFN-? producing capacity of pDCs was reduced after TLR9 stimulation, but increased when stimulated with a TLR7 agonist in SLE compared to in HC. IFN-? production by pDCs upon TLR9 stimulation was reduced and the percentage of IFN-?+pDC was inversely correlated with disease activity and serum IFN-? levels. However, the TLR7 agonist-induced IFN-? producing capacity of lupus pDCs was enhanced and correlated with disease activity and serum IFN-?. Exposure to IFN-? enhanced IFN-? 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.These findings indicate that enhanced TLR7 responses of lupus pDCs, owing to TLR7 retention in late endosome/lysosome and exposure to IFN-?, are associated with the pathogenesis of SLE.
SUBMITTER: Murayama G
PROVIDER: S-EPMC5649081 | biostudies-other | 2017 Oct
REPOSITORIES: biostudies-other
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