Keratin-dependent TSLP expression suggests a link between skin blistering and atopic disease. Mus musculus

Atopic dermatitis (AD) is a pruritic and inflammatory disorder characterized by elevated levels of thymic stromal lymphopoietin (TSLP). Pruritus is prevalent in epidermolysis bullosa (EB). Currently, epidermal barrier disruption is known to trigger TSLP upregulation, however, mechanisms controlling TSLP expression remain incompletely understood. Tslp levels were highly upregulated in the epidermis and in the serum of keratin-deficient mice. Cultured keratinocytes either lacking keratins or expressing the dominant K14p.Arg131Pro show highly increased TSLP. Re-expression of wild-type K14 normalized TSLP levels. We demonstrate that keratins regulate Tslp expression in parts through MEK1/2 activation. The finding that 8 out of 17 EBS patients show elevated TSLP serum levels supports a major role of keratins in TSLP regulation. Our data identify a novel, keratin-dependent and cell-intrinsic regulation of Tslp. Elevated TSLP levels likely explain the high prevalence of pruritus in EBS and additional forms of EB, suggesting TSLP as novel biomarker for pruritus in EB. MEK1/2, in addition to calcineurin inhibitors, might be suitable drugs to treat itch in EB. Overall design: Investigation was carried out using Keratin deficient keratinocytes isolated from typeI keratin mice.

特应性皮炎（Atopic Dermatitis, AD）是一类以胸腺基质淋巴细胞生成素（thymic stromal lymphopoietin, TSLP）水平升高为特征的瘙痒性炎症性疾病。瘙痒在大疱性表皮松解症（epidermolysis bullosa, EB）中具有高患病率。目前已知表皮屏障破坏可触发TSLP上调，但调控TSLP表达的具体机制仍未完全阐明。研究显示，角蛋白缺陷小鼠的表皮组织及血清中TSLP水平显著上调。体外培养的角蛋白缺失角质形成细胞，或表达显性突变K14p.Arg131Pro的角质形成细胞，其TSLP表达量均显著升高；而重新引入野生型K14可使TSLP水平恢复正常。本研究证实，角蛋白可部分通过激活丝裂原活化蛋白激酶激酶1/2（MEK1/2）通路调控TSLP的表达。17例单纯性大疱性表皮松解症（Epidermolysis Bullosa Simplex, EBS）患者中，有8例血清TSLP水平升高，这一发现支持了角蛋白在TSLP调控中发挥核心作用。本研究数据揭示了一种全新的、角蛋白依赖且细胞内在的TSLP表达调控机制。升高的TSLP水平或可解释EBS及其他亚型EB患者中瘙痒的高患病率，提示TSLP可作为EB患者瘙痒症状的新型生物标志物。除钙调神经磷酸酶抑制剂外，MEK1/2抑制剂或许可作为治疗EB相关性瘙痒的潜在药物。实验整体设计：本研究采用从I型角蛋白小鼠中分离得到的角蛋白缺陷角质形成细胞开展相关实验。