Kiatsurayanon Chanisa, Niyonsaba François, Smithrithee Rithee, Akiyama Toshihiro, Ushio Hiroko, Hara Mutsuko, Okumura Ko, Ikeda Shigaku, Ogawa Hideoki
Atopy (Allergy) Research Center, Juntendo University Graduate School of Medicine, Tokyo, Japan; Department of Dermatology, Juntendo University Graduate School of Medicine, Tokyo, Japan.
Atopy (Allergy) Research Center, Juntendo University Graduate School of Medicine, Tokyo, Japan.
J Invest Dermatol. 2014 Aug;134(8):2163-2173. doi: 10.1038/jid.2014.143. Epub 2014 Mar 14.
Human β-defensins (hBDs) are host defense peptides that not only exhibit microbicidal properties but also stimulate various cellular activities, including keratinocyte proliferation, migration, and wound healing. hBDs are overexpressed in the skin in cases of psoriasis but are downregulated in atopic dermatitis skin, although both diseases are associated with stratum corneum barrier defects. Because the tight-junction (TJ) barrier is also dysfunctional in both atopic dermatitis and psoriasis patients, we hypothesized that hBDs may regulate the TJ barrier function in keratinocytes. We observed that, among the hBDs tested, only hBD-3 increased the expression of several claudins and their localization along the cell-cell borders. In addition, hBD-3 elevated the transepithelial electrical resistance and reduced the paracellular permeability of keratinocyte layers, and this effect was reversed by the claudin inhibitor ochratoxin A, CCR6 antibody, and CCR6 small interfering RNA. Moreover, hBD-3 enhanced the activation of Rac1, atypical protein kinase C, glycogen synthase kinase-3, and phosphatidylinositol 3 kinase, which are required for the hBD-3-mediated regulation of the TJ barrier function, as evidenced by the effects of their respective inhibitors. Collectively, our findings provide evidence regarding the contribution of host defense peptides to the innate immunity of skin by regulating TJ barrier function, in addition to their antimicrobial and other immunomodulatory activities.
人β-防御素（hBDs）是宿主防御肽，不仅具有杀菌特性，还能刺激多种细胞活动，包括角质形成细胞的增殖、迁移和伤口愈合。尽管银屑病和特应性皮炎这两种疾病都与角质层屏障缺陷有关，但hBDs在银屑病患者的皮肤中过表达，而在特应性皮炎皮肤中表达下调。由于紧密连接（TJ）屏障在特应性皮炎和银屑病患者中也存在功能障碍，我们推测hBDs可能调节角质形成细胞中的TJ屏障功能。我们观察到，在所测试的hBDs中，只有hBD-3增加了几种闭合蛋白的表达及其沿细胞-细胞边界的定位。此外，hBD-3提高了角质形成细胞层的跨上皮电阻并降低了其细胞旁通透性，并且这种作用被闭合蛋白抑制剂赭曲霉毒素A、CCR6抗体和CCR6小干扰RNA所逆转。此外，hBD-3增强了Rac1、非典型蛋白激酶C、糖原合酶激酶-3和磷脂酰肌醇3激酶的激活，这些都是hBD-3介导的TJ屏障功能调节所必需的，其各自抑制剂的作用证明了这一点。总的来说，我们的研究结果提供了证据，表明宿主防御肽除了具有抗菌和其他免疫调节活性外，还通过调节TJ屏障功能对皮肤的固有免疫做出贡献。
