کد مقاله کد نشریه سال انتشار مقاله انگلیسی نسخه تمام متن
5648955 1407112 2016 12 صفحه PDF دانلود رایگان
عنوان انگلیسی مقاله ISI
Azithromycin impairs TLR7 signaling in dendritic cells and improves the severity of imiquimod-induced psoriasis-like skin inflammation in mice
موضوعات مرتبط
علوم پزشکی و سلامت پزشکی و دندانپزشکی امراض پوستی
پیش نمایش صفحه اول مقاله
Azithromycin impairs TLR7 signaling in dendritic cells and improves the severity of imiquimod-induced psoriasis-like skin inflammation in mice
چکیده انگلیسی

â¿¢Azithromycin (AZM) decreased the expression of co-stimulatory proteins and cytokines secretion in TLR7- activated dendritic cells.â¿¢AZM inhibited lysosomal acidification and disrupting proteolytic processing of TLR7 in imiquimod (IMQ) treated dendritic cells.â¿¢In IMQ-induced psoriasis-like mouse model, AZM decreased the IMQ-induced skin inflammation, reduced the hyperproliferation and restored the terminal differentiation of keratinocytes and decreased the accumulation of infiltrating immune cells in psoriatic skin.â¿¢AZM improved splenomegaly, diminished the Th17 cell population and reduced the expression of cytokines that are crucial for psoriasis in the skin and spleen.

BackgroundThe activation of Toll-like receptor 7 (TLR7) in dendritic cells (DCs) plays a crucial role in the pathogenesis of psoriasis. The macrolide antibiotic azithromycin (AZM) had been demonstrated to inhibit the TLR4 agonist-induced maturation and activation of murine bone marrow-derived DCs (BMDCs).ObjectiveTo investigate the effects of AZM on the induction of DC maturation and activation by imiquimod (IMQ), a synthetic TLR7 agonist, as well as its potential as a therapeutic agent for psoriasis.MethodsThe effects of AZM on IMQ-induced DC activation were investigated based on the expression of cell surface markers and cytokine secretion. The lysosomal pH, post-translational processing of TLR7, and TLR7 signaling were also examined in DCs. The therapeutic effects of AZM on psoriasis were evaluated in a murine model of IMQ-induced psoriasis-like skin inflammation.ResultsAZM significantly inhibited the expression of co-stimulatory molecules (CD40 and CD80) and reduced TNF-α, IL-10, IL-12p40, IL-12p70, IL-23p19 in BMDCs and IFN-α production in plasmacytoid DCs. AZM treatment impaired lysosomal acidification, interrupted TLR7 maturation in the lysosome, and ultimately blocked the IMQ-induced NF-κB and IRF-7 nuclear translocation in DCs. AZM treatment decreased signs of IMQ-induced skin inflammation in BALB/c mice. In addition to decreasing keratinocyte hyper-proliferation and restoring their terminal differentiation, AZM treatment decreased the accumulation of DCs as well as CD4, CD8 T cells and IL-17 producing cells in psoriatic skin lesions. AZM treatment improved splenomegaly, decreased the populations of Th17 and γδ T cells, and reduced the expression of cytokines known to be involved in the pathogenesis of psoriasis, such as IL-17A, IL-17F, IL-22 and IL-23, in the skin and spleen.ConclusionAZM impaired IMQ-induced DC activation by decreasing lysosomal acidification and disrupting TLR7 maturation and signaling. AZM significantly improved the IMQ-induced psoriasis-like inflammation in mice. AZM may be a potential therapeutic candidate for psoriasis treatment.

ناشر
Database: Elsevier - ScienceDirect (ساینس دایرکت)
Journal: Journal of Dermatological Science - Volume 84, Issue 1, October 2016, Pages 59-70
نویسندگان
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