Enhanced IFN-α production is associated with increased TLR7 retention in the lysosomes of palasmacytoid dendritic cells in systemic lupus erythematosus
Abstract Background Interferon-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 stimulate...
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| Format: | Article |
| Language: | English |
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BMC
2017-10-01
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| Series: | Arthritis Research & Therapy |
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| Online Access: | http://link.springer.com/article/10.1186/s13075-017-1441-7 |
| _version_ | 1818577711306637312 |
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| author | Goh Murayama Nanako Furusawa Asako Chiba Ken Yamaji Naoto Tamura Sachiko Miyake |
| author_facet | Goh Murayama Nanako Furusawa Asako Chiba Ken Yamaji Naoto Tamura Sachiko Miyake |
| author_sort | Goh Murayama |
| collection | DOAJ |
| description | Abstract Background Interferon-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. Methods pDCs 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. Results The 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. Conclusions These 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. |
| first_indexed | 2024-12-16T06:34:15Z |
| format | Article |
| id | doaj.art-33c7223d61ac485399eea9683130024a |
| institution | Directory Open Access Journal |
| issn | 1478-6362 |
| language | English |
| last_indexed | 2024-12-16T06:34:15Z |
| publishDate | 2017-10-01 |
| publisher | BMC |
| record_format | Article |
| series | Arthritis Research & Therapy |
| spelling | doaj.art-33c7223d61ac485399eea9683130024a2022-12-21T22:40:49ZengBMCArthritis Research & Therapy1478-63622017-10-0119111110.1186/s13075-017-1441-7Enhanced IFN-α production is associated with increased TLR7 retention in the lysosomes of palasmacytoid dendritic cells in systemic lupus erythematosusGoh Murayama0Nanako Furusawa1Asako Chiba2Ken Yamaji3Naoto Tamura4Sachiko Miyake5Department of Immunology, Juntendo University School of MedicineDepartment of Immunology, Juntendo University School of MedicineDepartment of Immunology, Juntendo University School of MedicineDepartment of Internal Medicine and Rheumatology, Juntendo University School of MedicineDepartment of Internal Medicine and Rheumatology, Juntendo University School of MedicineDepartment of Immunology, Juntendo University School of MedicineAbstract Background Interferon-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. Methods pDCs 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. Results The 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. Conclusions These 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.http://link.springer.com/article/10.1186/s13075-017-1441-7Systemic lupus erythematosusToll-like receptorInterferon-αPlasmacytoid dendritic cells |
| spellingShingle | Goh Murayama Nanako Furusawa Asako Chiba Ken Yamaji Naoto Tamura Sachiko Miyake Enhanced IFN-α production is associated with increased TLR7 retention in the lysosomes of palasmacytoid dendritic cells in systemic lupus erythematosus Arthritis Research & Therapy Systemic lupus erythematosus Toll-like receptor Interferon-α Plasmacytoid dendritic cells |
| title | Enhanced IFN-α production is associated with increased TLR7 retention in the lysosomes of palasmacytoid dendritic cells in systemic lupus erythematosus |
| title_full | Enhanced IFN-α production is associated with increased TLR7 retention in the lysosomes of palasmacytoid dendritic cells in systemic lupus erythematosus |
| title_fullStr | Enhanced IFN-α production is associated with increased TLR7 retention in the lysosomes of palasmacytoid dendritic cells in systemic lupus erythematosus |
| title_full_unstemmed | Enhanced IFN-α production is associated with increased TLR7 retention in the lysosomes of palasmacytoid dendritic cells in systemic lupus erythematosus |
| title_short | Enhanced IFN-α production is associated with increased TLR7 retention in the lysosomes of palasmacytoid dendritic cells in systemic lupus erythematosus |
| title_sort | enhanced ifn α production is associated with increased tlr7 retention in the lysosomes of palasmacytoid dendritic cells in systemic lupus erythematosus |
| topic | Systemic lupus erythematosus Toll-like receptor Interferon-α Plasmacytoid dendritic cells |
| url | http://link.springer.com/article/10.1186/s13075-017-1441-7 |
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