Protein engineering of the chemokine CCL20 prevents psoriasiform dermatitis in an IL-23-dependent murine model
Protein engineering of the chemokine CCL20 prevents psoriasiform dermatitis in an IL-23-dependent murine model
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DOI：
10.1073/pnas.1704958114
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发表时间：
2017-11-21
影响因子：
11.1
通讯作者：
Volkman, B. F.
中科院分区：
文献类型：
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作者：
Getschman, A. E.;Imai, Y.;Volkman, B. F.
银屑病是一种慢性炎症性皮肤病，其特征是T细胞和其他免疫细胞对损伤或自身抗原的反应渗入皮肤。通过CCL20和其他趋化因子，常规和非常规的伽马(增量)T细胞被招募到真皮和表皮。CCL20与其受体CCR6一起，在小鼠银屑病样皮炎的发生发展中起关键作用。我们筛选了一组CCL20变体，这些变体旨在形成由分子间二硫键稳定的二聚体。单原子置换产生CCL20变异体(CCL20 S64C)，作为趋化因子受体CCR6的部分激动剂。CCL20 S64C结合CCR6并诱导细胞内钙释放，与G蛋白激活一致，但趋化活性最低。相反，CCL20 S64C抑制了CCR6介导的T细胞迁移，并名义上影响了其他趋化因子受体信号。当在依赖IL-23的银屑病小鼠模型中给予CCL20 S64C时，CCL20 S64C可以预防银屑病炎症以及IL-17A和IL-22的上调。我们的结果证实了CCR6是治疗银屑病的易治疗靶点，并证明了CCL20 S64C作为先导化合物的价值。
Psoriasis is a chronic inflammatory skin disease characterized by the infiltration of T cell and other immune cells to the skin in response to injury or autoantigens. Conventional, as well as unconventional, gamma(delta) T cells are recruited to the dermis and epidermis by CCL20 and other chemokines. Together with its receptor CCR6, CCL20 plays a critical role in the development of psoriasiform dermatitis in mouse models. We screened a panel of CCL20 variants designed to form dimers stabilized by intermolecular disulfide bonds. A single-atom substitution yielded a CCL20 variant (CCL20 S64C) that acted as a partial agonist for the chemokine receptor CCR6. CCL20 S64C bound CCR6 and induced intracellular calcium release, consistent with G-protein activation, but exhibited minimal chemotactic activity. Instead, CCL20 S64C inhibited CCR6-mediated T cell migration with nominal impact on other chemokine receptor signaling. When given in an IL-23-dependent mouse model for psoriasis, CCL20 S64C prevented psoriatic inflammation and the up-regulation of IL-17A and IL-22. Our results validate CCR6 as a tractable therapeutic target for psoriasis and demonstrate the value of CCL20 S64C as a lead compound.