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

Xie, Xiangjiang; Di, Tingting; Wang, Yan; Wang, Mingxing; Meng, Yukun; Lin, Ye; Xu, Xiaolong; Li, Ping; Zhao, Jingxia

doi:10.1016/j.molimm.2018.07.011

Cited by 39 publications

(19 citation statements)

References 31 publications

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“…A 12/12 h light/dark cycle used for all rats. The rats were euthanized through intraperitoneal injection of a mixture solution of ketamine (87.5 mg/kg) and xylazine (12.5 mg/kg), and the bone marrow aspirates were separated and cultivated by the plastic adherence method (18). All experiments using rats were approved by the Medical Research Ethics Committee of Chongqing Medical University for the Ethics of Animal Experiments of Chongqing Medical University.…”

Section: Methodsmentioning

confidence: 99%

IL22 furthers malignant transformation of rat mesenchymal stem cells, possibly in association with IL22RA1/STAT3 signaling

Cui

Xuan

et al. 2019

Oncol Rep

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Mesenchymal stem cells (MSCs) hold great promise as potential therapies for tumors through the delivery of various anticancer agents. However, exogenous tissue-derived MSCs, such as those of bone marrow, have exhibited a tendency for malignant transformation in the tumor microenvironment. This issue remains controversial and is poorly understood. In the present study, the role of interleukin 22 (IL22)/IL22 receptor subunit α 1 (IL22RA1) and signal transducer and activator of transcription 3 (STAT3) signaling in the malignant transformation of MSCs was investigated. Following isolation of rat MSCs and their indirect co-culture with C6 glioma cells, the transformed MSCs exhibited tumor cell characteristics. The Cancer Genome Atlas-Glioblastoma Multiforme analysis revealed that primary and recurrent glioblastomas have increased IL22RA1 expression, compared with normal tissues, whereas the expression of IL22 was low in glioblastoma and normal tissues. mRNA and protein expression levels of IL22RA1 were significantly increased in the MSCs co-cultured with C6 glioma cells. Furthermore, MSCs incubated with IL22 exhibited increased proliferation, migration and invasion. STAT3 demonstrated activation and nuclear translocation in the presence of IL22. Additionally, STAT3 small interfering RNA significantly inhibited the migration and invasion ability of MSCs, and the expression of the STAT3 downstream targets cyclin D1 and B-cell lymphoma-extra large under IL22 stimulation, indicating that IL22 also promoted MSC migration and invasion through STAT3 signaling. These data indicated that IL22 serves a critical role in the malignant transformation of rat MSCs, which is associated with an enhancement of the IL22RA1/STAT3 signaling pathway in the tumor microenvironment.

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Section: Methodsmentioning

confidence: 99%

IL22 furthers malignant transformation of rat mesenchymal stem cells, possibly in association with IL22RA1/STAT3 signaling

Cui

Xuan

et al. 2019

Oncol Rep

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“…Among various beneficial phytochemicals, indigo naturalis extract and its salubrious component indirubin have drawn particular attention because they have been shown to exert potent anti-inflammatory effects in mouse models of inflammatory epithelial disorders, such as psoriasis and ulcerative colitis 7,14,25,26 . In these mouse models, indirubin inhibits the proliferation and accelerates the differentiation of keratinocytes 7 and induces Foxp3-expressing regulatory T cells 26 .…”

Section: Discussionmentioning

confidence: 99%

Indirubin-pregnane X receptor-JNK axis accelerates skin wound healing

Tanaka

Uchi

Ito

et al. 2019

Sci Rep

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Indirubin is a potent anti-inflammatory phytochemical derived from indigo naturalis. It is also endogenously produced in the intestine and detected in the circulation in mammals. Indirubin exerts its biological functions via two xenobiotic receptor systems: aryl hydrocarbon receptor (AHR) and pregnane X receptor (PXR); however, its effects on wound healing remain elusive. To investigate whether indirubin promotes wound healing, we utilized an in vitro scratch injury assay and in vivo full-thickness mouse skin ulcer model and assessed wound closure. Indirubin significantly accelerated wound closure in both the scratch assay and the skin ulcer model. Using inhibitors of cell proliferation or migration, indirubin was found to upregulate the migratory but not the proliferative capacity of keratinocytes. Activation of AHR/PXR by indirubin was confirmed by their nuclear translocation and subsequent upregulation of CYP1A1 (AHR), or UGT1A1 mRNA (PXR) and also by luciferase reporter assay (PXR). Although both AHR and PXR were activated by indirubin, its pro-migratory capacity was canceled by PXR inhibition but not by AHR inhibition and was dependent on the JNK pathway. Moreover, activated PXR was detected in the nuclei of re-epithelialized keratinocytes in human skin ulcers. In conclusion, this study shows that the indirubin-PXR-JNK pathway promotes skin wound healing.

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“…Indirubin (IR) is a bisindole compound extracted from the leaves of the Chinese herb Indigo naturalis. It has been demonstrated to alleviate IMQ-induced psoriasis-like dermatitis by primarily reducing the inflammatory responses mediated by IL-17 A-producing gdT cells through Jak3/Stat3 activation (153). Dashlkhumbe et al reported a newly formulated methotrexate (MTX, a chemical conjugate of MTX with a cell-permeable peptide) for the treatment of psoriasis.…”

Section: Targeting Gdt Cells For Psoriasis Therapymentioning

confidence: 99%

Gamma Delta T Cells and Their Pathogenic Role in Psoriasis

Qian

Wang

et al. 2021

Front. Immunol.

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γδT cells are an unconventional population of T lymphocytes that play an indispensable role in host defense, immune surveillance, and homeostasis of the immune system. They display unique developmental, distributional, and functional patterns and rapidly respond to various insults and contribute to diverse diseases. Although γδT cells make up only a small portion of the total T cell pool, emerging evidence suggest that aberrantly activated γδT cells may play a role in the pathogenesis of psoriasis. Dermal γδT cells are the major IL-17-producing cells in the skin that respond to IL-23 stimulation. Furthermore, γδT cells exhibit memory-cell-like characteristics that mediate repeated episodes of psoriatic inflammation. This review discusses the differentiation, development, distribution, and biological function of γδT cells and the mechanisms by which they contribute to psoriasis. Potential therapeutic approaches targeting these cells in psoriasis have also been detailed.

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

Cited by 39 publications

References 31 publications

IL22 furthers malignant transformation of rat mesenchymal stem cells, possibly in association with IL22RA1/STAT3 signaling

IL22 furthers malignant transformation of rat mesenchymal stem cells, possibly in association with IL22RA1/STAT3 signaling

Indirubin-pregnane X receptor-JNK axis accelerates skin wound healing

Gamma Delta T Cells and Their Pathogenic Role in Psoriasis

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