Indirubin ameliorates imiquimod-induced psoriasis-like skin lesions in mice by inhibiting inflammatory responses mediated by IL-17A-producing γδ T cells

• Published in: Molecular immunology 2018-09, Vol.101, p.386-395
• Main Authors: Xie, Xiang-jiang, Di, Ting-ting, Wang, Yan, Wang, Ming-xing, Meng, Yu-jiao, Lin, Yan, Xu, Xiao-long, Li, Ping, Zhao, Jing-xia
• Format: Article
• Language: English
• Subjects: Animals; Cell Proliferation - drug effects; Cytokines - genetics; Cytokines - metabolism; Disease Models, Animal; IL-17A; Imiquimod - adverse effects; Indirubin; Indoles - chemistry; Indoles - pharmacology; Indoles - therapeutic use; Inflammation - pathology; Inflammation Mediators - metabolism; Interleukin-17 - biosynthesis; Jak3/Stat3; Janus Kinase 3 - metabolism; Keratinocytes - drug effects; Keratinocytes - pathology; Lymph Nodes - drug effects; Lymph Nodes - metabolism; Male; Mice, Inbred BALB C; Phosphorylation - drug effects; Psoriasis; Psoriasis - chemically induced; Psoriasis - drug therapy; Psoriasis - genetics; Psoriasis - immunology; Receptors, Antigen, T-Cell, gamma-delta - metabolism; RNA, Messenger - genetics; RNA, Messenger - metabolism; Signal Transduction - drug effects; Skin - pathology; STAT3 Transcription Factor - metabolism; Th17 Cells - immunology; γδT cell
• ISSN: 0161-5890; 1872-9142
• DOI: 10.1016/j.molimm.2018.07.011

•Indirubin alleviates IMQ-induced psoriasis-like inflammation.•The production of γδ T cell and CCR6 γδ T in the spleen and lymph nodes changed in indirubin treated mice.•Indirubin suppressed IL-17 A expression and secretion, and Jak3/Stat3 activation in in vitro cultured γδ T cells. Indirubin (IR) is a bisindole compound extracted from the leaves of Chinese herb Indigo Naturalis. Indigo Naturalis has been widely used in traditional Chinese medicine to treat inflammatory and autoimmune diseases. Psoriasis is a chronic immune-mediated inflammatory skin disease in which γδ T cells play an important role. This study aims to determine the immunoregulatory effects and the underlying mechanisms of Indirubin in psoriasis-related inflammatory responses. BALB/c mice with imiquimod (IMQ)-induced psoriasis-like dermatitis were treated with saline (Model), 1 mg/kg methotrexate (MTX) that serves as a positive control, or 12.5, 25 and 50 mg/kg Indirubin(IR) intragastrically. Keratinocytes proliferation, inflammatory cells infiltration, the expression of inflammatory cytokines and Jak/Stat pathway-related proteins in the skin lesion were examined. The abundance of γδ T cells in lymph nodes and spleen was determined by flow cytometry. The IL-17 expression and secretion, and the activation of Jak3/Stat3 pathways in in vitro cultured γδ T cell were tested. Indirubin ameliorated keratinocyte proliferation, reduced the infiltration of CD3+ T cells, IL-17 A-producing γδ T cells, and CD11b+ neutrophils, inhibited the mRNA expression of Il1, Il6, Il23, Il17a and Il22, and the protein expression of Jak/Stat pathway-related molecules in the skin lesion. Indirubin also reduced the abundance of γδ T cell and CCR6+ γδ T cells (the major IL-17 A producer) in spleen and lymph nodes. In cultured γδ T cells, Indirubin inhibited the mRNA expression of Il17a and Ifng, and the secretion of IL-17 A, while suppressed the activation of Jak3/Stat3 pathways. Indirubin alleviates IMQ-induced psoriasis-like dermatitis mainly through reducing the inflammatory responses mediated by IL-17 A-producing γδ T cells involving Jak3/Stat3 activation. Our results highlighted the novel mechanisms by which Indirubin ameliorates psoriasis-related inflammatory responses, supporting its therapeutic potential.