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Xenobiotic Receptor CAR Is Highly Induced in Psoriasis and Promotes Keratinocyte Proliferation

  • Author Footnotes
    6 These authors contributed equally to this work.
    Baochang Lai
    Footnotes
    6 These authors contributed equally to this work.
    Affiliations
    Cardiovascular Research Center, School of Basic Medical Sciences, Xi’an Jiaotong University, Xi’an, China
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  • Author Footnotes
    6 These authors contributed equally to this work.
    Xinya Xie
    Footnotes
    6 These authors contributed equally to this work.
    Affiliations
    Cardiovascular Research Center, School of Basic Medical Sciences, Xi’an Jiaotong University, Xi’an, China
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  • Author Footnotes
    6 These authors contributed equally to this work.
    Fan Li
    Footnotes
    6 These authors contributed equally to this work.
    Affiliations
    Cardiovascular Research Center, School of Basic Medical Sciences, Xi’an Jiaotong University, Xi’an, China
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  • Qi Cui
    Affiliations
    Advanced Institute for Medical Sciences, Dalian Medical University, Dalian, China
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  • Erle Dang
    Affiliations
    Department of Dermatology, Xijing Hospital, Air Force Medical University, Xi'an, China
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  • Wenhuan Luo
    Affiliations
    Advanced Institute for Medical Sciences, Dalian Medical University, Dalian, China
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  • Ning Wang
    Affiliations
    Department of Dermatology, The Second Affiliated Hospital, Xi’an Jiaotong University, Xi’an, China
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  • Yan Zheng
    Affiliations
    Department of Dermatology, The Second Affiliated Hospital, Xi’an Jiaotong University, Xi’an, China
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  • Gang Wang
    Affiliations
    Department of Dermatology, Xijing Hospital, Air Force Medical University, Xi'an, China
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  • Author Footnotes
    7 These authors contributed equally to this work.
    Lei Xiao
    Correspondence
    Correspondence: Lei Xiao, Cardiovascular Research Center, School of Basic Medical Sciences, Xi’an Jiaotong University, Xi’an 710061, China.
    Footnotes
    7 These authors contributed equally to this work.
    Affiliations
    Cardiovascular Research Center, School of Basic Medical Sciences, Xi’an Jiaotong University, Xi’an, China

    Key Laboratory of Environment and Genes Related to Diseases, Xi’an Jiaotong University, Ministry of Education of China, Xi’an, China
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  • Author Footnotes
    7 These authors contributed equally to this work.
    Nanping Wang
    Footnotes
    7 These authors contributed equally to this work.
    Affiliations
    Advanced Institute for Medical Sciences, Dalian Medical University, Dalian, China
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  • Author Footnotes
    6 These authors contributed equally to this work.
    7 These authors contributed equally to this work.
      Psoriasis is a chronic inflammatory skin disease with abnormal epidermal proliferation. Xenobiotics contribute to the pathogenesis of psoriasis. The mechanism linking xenobiotic stimuli with epidermal proliferation remains largely unknown. In this study, we investigated the role of CAR, a nuclear receptor (NR1I3) responsible for xenobiotics detoxification. We showed that CAR and its target genes were induced in the lesions from patients with psoriasis and imiquimod-treated mice. Proinflammatory cytokines (IL-17A, IL-22, oncostatin M, IL-1α, and TNF-α) synergistically increased the expressions of CAR and its target genes in both human and mouse keratinocytes. Overexpression of CAR promoted the G1/S transition by regulating cyclin E and c-Myc expressions, whereas the silencing of CAR attenuated it. Importantly, a selective CAR agonist 6-(4-chlorophenyl)imidazo(2,1-b)(1,3)thiazole-5-carbaldehyde O-(3,4-dichlorobenzyl)oxime or the proinflammatory cytokines induced cyclin E and c-Myc, which were largely blocked by clotrimazole, a selective CAR antagonist, or CAR small interfering RNA. In addition, we showed that topical application of 1,4-bis[2-(3,5-dichloropyridyloxy)]benzene, a selective agonist for mouse CAR, exacerbated the IMQ-induced psoriasis lesions with increased expressions of proliferative and inflammatory markers. In contrast, Car-knockout mice developed significantly milder lesions. In conclusion, these results showed that CAR plays a pathogenic role and, potentially, may be a target for the treatment of psoriasis.

      Abbreviations:

      CITCO (6-(4-chlorophenyl)imidazo(2,1-b)(1,3)thiazole-5-carbaldehyde O-(3,4-dichlorobenzyl)oxime), IMQ (imiquimod), KC (keratinocyte), NHEK (normal human epidermal keratinocyte), TCPOBOP (1,4-bis[2-(3,5-Dichloropyridyloxy)]benzene)
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