Azithromycin impairs TLR7 signaling in dendritic cells and improves the severity of imiquimod-induced psoriasis-like skin inflammation in mice Shi-Wei Huang a,1 , Yi-Ju Chen b,c,1 , Sin-Ting Wang d , Li-Wei Ho d,e , Jun-Kai Kao d,e , Miwako Narita f ,g , Masuhiro Takahashi f , Chun-Ying Wu c,h , Hsuan-Yu Cheng d , Jeng-Jer Shieh a,d,i , * a Department of Education and Research, Taichung Veterans General Hospital, Taichung, Taiwan b Department of Dermatology, Taichung Veterans General Hospital, Taichung, Taiwan c Faculty of Medicine, National Yang Ming University, Taipei, Taiwan d Institute of Biomedical Sciences, National Chung Hsing University, Taichung, Taiwan e Department of Pediatrics, Children’s Hospital, Changhua Christian Hospital, Changhua, Taiwan f Laboratory of Hematology and Oncology, Graduate School of Health Sciences, Niigata University, Niigata, Japan g Division of Hematology, Graduate School of Medical and Dental Sciences, Niigata University, Niigata, Japan h Division of Gastroenterology and Hepatology, Taichung Veterans General Hospital, Taichung, Taiwan i Rong Hsing Research Center for Translational Medicine, National Chung Hsing University, Taichung, Taiwan A R T I C L E I N F O Article history: Received 31 December 2015 Received in revised form 6 May 2016 Accepted 12 July 2016 Keywords: Azithromycin Imiquimod Toll-like receptor 7 Psoriasis A B S T R A C T Background: The 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). Objective: To 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. Methods: The 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. Results: AZM significantly inhibited the expression of co-stimulatory molecules (CD40 and CD80) and reduced TNF-a, IL-10, IL-12p40, IL-12p70, IL-23p19 in BMDCs and IFN-a production in plasmacytoid DCs. AZM treatment impaired lysosomal acidification, interrupted TLR7 maturation in the lysosome, and ultimately blocked the IMQ-induced NF-kB 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 gd 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. Conclusion: AZM 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. ã 2016 Japanese Society for Investigative Dermatology. Published by Elsevier Ireland Ltd. All rights reserved. 1. Introduction Dendritic cells (DCs) are professional antigen-presenting cells that link the innate and adaptive immune systems [1]. DCs exist as heterogeneous populations. All DCs share the ability to activate * Corresponding author at: Room 116A, Research Building, Taichung Veterans General Hospital, No. 160, Sec. 3, Chung-Kang Rd., Taichung 407, Taiwan. E-mail addresses: shiehjj@vghtc.gov.tw, shiehjj@dragon.nchu.edu.tw (J.-J. Shieh). 1 These authors contributed equally to this work. http://dx.doi.org/10.1016/j.jdermsci.2016.07.007 0923-1811/ ã 2016 Japanese Society for Investigative Dermatology. Published by Elsevier Ireland Ltd. All rights reserved. Journal of Dermatological Science xxx (2016) xxx–xxx G Model DESC 3030 No. of Pages 12 Please cite this article in press as: S.-W. Huang, et al., Azithromycin impairs TLR7 signaling in dendritic cells and improves the severity of imiquimod-induced psoriasis-like skin inflammation in mice, J Dermatol Sci (2016), http://dx.doi.org/10.1016/j.jdermsci.2016.07.007 Contents lists available at ScienceDirect Journal of Dermatological Science journa l home page : www.jdsjournal.com