title: Azithromycin impairs TLR7 signaling in dendritic cells and improves the severity of imiquimod-induced psoriasis-like skin inflammation in mice.
abstract: 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-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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Department of Education and Research, Taichung Veterans General Hospital, Taichung, Taiwan.
authors.forename: Shi-Wei
authors.initials: SW
authors.lastname: Huang
authors.affiliation: Department of Dermatology, Taichung Veterans General Hospital, Taichung, Taiwan; Faculty of Medicine, National Yang Ming University, Taipei, Taiwan.
authors.forename: Yi-Ju
authors.initials: YJ
authors.lastname: Chen
authors.affiliation: Institute of Biomedical Sciences, National Chung Hsing University, Taichung, Taiwan.
authors.forename: Sin-Ting
authors.initials: ST
authors.lastname: Wang
authors.affiliation: Institute of Biomedical Sciences, National Chung Hsing University, Taichung, Taiwan; Department of Pediatrics, Children's Hospital, Changhua Christian Hospital, Changhua, Taiwan.
authors.forename: Li-Wei
authors.initials: LW
authors.lastname: Ho
authors.affiliation: Institute of Biomedical Sciences, National Chung Hsing University, Taichung, Taiwan; Department of Pediatrics, Children's Hospital, Changhua Christian Hospital, Changhua, Taiwan.
authors.forename: Jun-Kai
authors.initials: JK
authors.lastname: Kao
authors.affiliation: Laboratory of Hematology and Oncology, Graduate School of Health Sciences, Niigata University, Niigata, Japan; Division of Hematology, Graduate School of Medical and Dental Sciences, Niigata University, Niigata, Japan.
authors.forename: Miwako
authors.initials: M
authors.lastname: Narita
authors.affiliation: Laboratory of Hematology and Oncology, Graduate School of Health Sciences, Niigata University, Niigata, Japan.
authors.forename: Masuhiro
authors.initials: M
authors.lastname: Takahashi
authors.affiliation: Faculty of Medicine, National Yang Ming University, Taipei, Taiwan; Division of Gastroenterology and Hepatology, Taichung Veterans General Hospital, Taichung, Taiwan.
authors.forename: Chun-Ying
authors.initials: CY
authors.lastname: Wu
authors.affiliation: Institute of Biomedical Sciences, National Chung Hsing University, Taichung, Taiwan.
authors.forename: Hsuan-Yu
authors.initials: HY
authors.lastname: Cheng
authors.affiliation: Department of Education and Research, Taichung Veterans General Hospital, Taichung, Taiwan; Institute of Biomedical Sciences, National Chung Hsing University, Taichung, Taiwan; Rong Hsing Research Center for Translational Medicine, National Chung Hsing University, Taichung, Taiwan. Electronic address: shiehjj@vghtc.gov.tw.
authors.forename: Jeng-Jer
authors.initials: JJ
authors.lastname: Shieh
mesh_terms: D000634:Aminoquinolines; D000818:Animals; D000900:Anti-Bacterial Agents / Q000737:chemistry; D017963:Azithromycin / Q000494:pharmacology*; D049109:Cell Proliferation; D016207:Cytokines / Q000378:metabolism; D003713:Dendritic Cells / Q000166:cytology* / Q000378:metabolism; D004195:Disease Models, Animal; D005260:Female; D006801:Humans; D000077271:Imiquimod; D015603:Keratinocytes / Q000166:cytology; D007963:Leukocytes, Mononuclear / Q000166:cytology; D008247:Lysosomes / Q000378:metabolism; D008562:Membrane Glycoproteins / Q000378:metabolism*; D051379:Mice; D008807:Mice, Inbred BALB C; D011565:Psoriasis / Q000276:immunology* / Q000378:metabolism*; D015398:Signal Transduction; D012867:Skin / Q000378:metabolism* / Q000473:pathology; D013154:Spleen / Q000378:metabolism; D058504:Th17 Cells / Q000166:cytology; D051199:Toll-Like Receptor 7 / Q000378:metabolism*
chemical_list: D000634:Aminoquinolines; D000900:Anti-Bacterial Agents; D016207:Cytokines; D008562:Membrane Glycoproteins; C477038:Tlr7 protein, mouse; D051199:Toll-Like Receptor 7; D017963:Azithromycin; D000077271:Imiquimod
keywords: Azithromycin; Imiquimod; Psoriasis; Toll-like receptor 7