XENOBIOTIC CONSTITUTIVE ANDROSTANE RECEPTOR (CAR) IS HIGHLY INDUCED IN PSORIASIS AND PROMOTES KERATINOCYTE PROLIFERATION
XENOBIOTIC CONSTITUTIVE ANDROSTANE RECEPTOR (CAR) IS HIGHLY INDUCED IN PSORIASIS AND PROMOTES KERATINOCYTE PROLIFERATION
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异生雄烷受体 (CAR) 在银屑病中高度诱导并促进角质形成细胞增殖
DOI：
10.1016/j.jid.2021.05.017
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发表时间：
2021
影响因子：
6.5
通讯作者：
Nanping Wang
中科院分区：
文献类型：
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作者：
Baochang Lai;Xinya Xie;Fan Li;Qi Cui;Erle Dang;Wenhuan Luo;Ning Wang;Yan Zheng;Gang Wang;Lei Xiao;Nanping Wang
银屑病是一种表皮异常增生的慢性炎症性皮肤病。外源性物质有助于银屑病的发病机制。外源性刺激与表皮增殖的联系机制在很大程度上仍然未知。在这项研究中，我们研究了CAR的作用，CAR是一种核受体（NR 1 I3），负责外源性物质的解毒。我们发现CAR及其靶基因在银屑病患者和咪喹莫特治疗小鼠的病变中被诱导。促炎细胞因子IL-17 A、IL-22、抑瘤素M、IL-1α和TNF-α协同增加人和小鼠角质形成细胞中CAR及其靶基因的表达。CAR的过表达通过调节细胞周期蛋白E和c-Myc表达促进G1/S转换，而CAR的沉默则减弱了它。重要的是，选择性CAR激动剂6-（4-氯苯基）咪唑并（2，1-B）（1，3）噻唑-5-甲醛O-（3，4-二氯苄基）肟或促炎细胞因子诱导细胞周期蛋白E和c-Myc，其在很大程度上被克霉唑（选择性CAR拮抗剂）或CAR小干扰RNA阻断。此外，我们发现局部应用1，4-双[2-（3，5-二氯吡啶氧基）]苯（一种小鼠CAR的选择性激动剂）加剧了IMQ诱导的银屑病病变，并增加了增殖和炎症标志物的表达。相比之下，Car基因敲除小鼠的病变明显较轻。总之，这些结果表明CAR起着致病作用，并且可能是治疗银屑病的靶点。
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.