Epidermal barrier defects link atopic dermatitis with altered skin cancer susceptibility.
Epidermal barrier defects link atopic dermatitis with altered skin cancer susceptibility.
复制标题
表皮屏障缺陷将特应性皮炎与皮肤癌敏感性改变。
DOI：
10.7554/elife.01888
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发表时间：
2014-05-05
期刊：
影响因子：
7.7
通讯作者：
Watt FM
中科院分区：
文献类型：
--
作者：
Cipolat S;Hoste E;Natsuga K;Quist SR;Watt FM
特应性皮炎可能是由于最外层的表皮层中的结构蛋白丢失，导致表皮屏障缺陷所致。为了测试这是否会影响肿瘤的形成，我们在EPI−/−小鼠身上进行了化学诱导肿瘤，这种小鼠缺乏三种屏障蛋白-Envoplakin、Periplakin和Involucrin。用7，12-二甲基苯并(A)菲和12-O-十四烷基佛波醇-13-醋酸酯处理的EPI−/−小鼠对良性肿瘤的抵抗力很强。DMBA反应正常，但EPI−/−皮肤对TPA表现出夸大的特应性反应，其特征是表皮分化异常，复杂的免疫浸润和血清胸腺基质淋巴生成素(TSLP)升高。通过阻断TSLP或免疫受体NKG2D，但不能阻断CD4+T细胞，加剧的TPA反应可以正常化。我们得出结论，在我们的实验模型中，特应性是预防皮肤癌的，其机制涉及角质形成细胞通过通常保护免受环境攻击的信号元件与免疫系统的细胞进行通信。DOI：http://dx.doi.org/10.7554/eLife.01888.001皮肤癌是一个常见且日益严重的问题--根据世界卫生组织的数据，全球确诊的癌症中，皮肤癌占三分之一。流行病学研究有一些证据表明，某些过敏症患者可能对癌症有保护作用，特别是过敏性皮肤状况特应性皮炎与各种皮肤癌水平的降低有关。然而，很难知道这种减少是由于特应性皮炎本身还是由于治疗这种过敏的药物。缺乏参与角化包膜形成的三种蛋白质的基因工程小鼠，可以用来研究特应性皮炎。角化包膜是取代最外层细胞中正常质膜的保护层。这些“三重基因敲除小鼠”的表皮屏障存在缺陷，皮肤中的免疫T细胞水平也发生了变化。现在，西波拉特等人。研究了表皮屏障的缺陷是否能预防皮肤癌。基因敲除小鼠和野生型小鼠接受了两种化学物质的治疗：DMBA和TPA，前者会导致一种名为HRAS的基因发生突变，后者会促进含有HRAS突变的细胞形成肿瘤。大约16周后，几乎所有野生型小鼠都至少有一个良性肿瘤，而一半的基因敲除小鼠没有肿瘤。总体而言，野生型小鼠平均每只小鼠患良性肿瘤的数量是后者的6倍。这表明，在基因敲除小鼠中导致表皮屏障缺陷的突变也可以保护它们免受DMBA和TPA联合作用引起的肿瘤的影响。Cipolat等人。然后比较了小鼠对DMBA或TPA单独的反应。基因敲除小鼠和野生型小鼠对DMBA的反应方式相同；然而，基因敲除小鼠对TPA表现出夸大的反应，包括强烈的炎症反应。这种反应包括产生更高水平的各种蛋白质，这些蛋白质参与皮肤细胞和免疫系统之间的通讯。Cipolat等人。提出由这种夸大的反应引起的免疫反应可能有助于通过消除皮肤中的肿瘤形成细胞来防止肿瘤的形成。DOI：http://dx.doi.org/10.7554/eLife.01888.002
Atopic dermatitis can result from loss of structural proteins in the outermost epidermal layers, leading to a defective epidermal barrier. To test whether this influences tumour formation, we chemically induced tumours in EPI−/− mice, which lack three barrier proteins—Envoplakin, Periplakin, and Involucrin. EPI−/− mice were highly resistant to developing benign tumours when treated with 7,12-dimethylbenz(a)anthracene (DMBA) and 12-O-tetradecanoylphorbol-13-acetate (TPA). The DMBA response was normal, but EPI−/− skin exhibited an exaggerated atopic response to TPA, characterised by abnormal epidermal differentiation, a complex immune infiltrate and elevated serum thymic stromal lymphopoietin (TSLP). The exacerbated TPA response could be normalised by blocking TSLP or the immunoreceptor NKG2D but not CD4+ T cells. We conclude that atopy is protective against skin cancer in our experimental model and that the mechanism involves keratinocytes communicating with cells of the immune system via signalling elements that normally protect against environmental assaults. DOI: http://dx.doi.org/10.7554/eLife.01888.001 Skin cancer is a common and growing problem—according to the World Health Organization, skin cancers account for one in every three cancers diagnosed world wide. There is some evidence from epidemiological studies that patients with certain allergies might be protected against cancer and, in particular, that the allergic skin condition atopic dermatitis is associated with reduced levels of various skin cancers. However, it is difficult to know if this reduction is due to the atopic dermatitis itself or to the drugs used to treat this allergy. Genetically engineered mice that are lacking three proteins that are involved in the formation of the cornified envelope—the protective layer that replaces the normal plasma membrane in the cells of the outermost skin layers—can be used to study atopic dermatitis. These ‘triple knockout mice’ have a defective epidermal barrier and altered levels of immune T-cells in the skin. Now Cipolat et al. have investigated whether defects in the epidermal barrier protect against skin cancer. Knockout mice and wild-type mice were treated with two chemicals: DMBA, which causes mutations in a gene called HRas, and TPA, which promotes the formation of tumours from cells that contain HRas mutations. After about 16 weeks almost all of the wild-type mice had at least one benign tumour, whereas half of the knockout mice had no tumours. Overall, the average number of benign tumours per mouse was six times higher in the wild-type mice. This shows that the mutations that cause the epidermal barrier defects in knockout mice also protect them against the tumours caused by the combined effects of DMBA and TPA. Cipolat et al. then compared how the mice responded to DMBA or TPA alone. The knockout mice and the wild-type mice responded to DMBA in the same way; however, the knockout mice showed an exaggerated response to TPA, including a strong inflammatory reaction. This response comprised the production of higher levels of various proteins that are involved in communications between skin cells and the immune system. Cipolat et al. propose that the immune reaction caused by this exaggerated response could help to prevent tumour formation by eliminating tumour-forming cells in the skin. DOI: http://dx.doi.org/10.7554/eLife.01888.002