RAC1 activation drives pathologic interactions between the epidermis and immune cells
RAC1 activation drives pathologic interactions between the epidermis and immune cells
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DOI：
10.1172/jci85738
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发表时间：
2016-07-01
影响因子：
15.9
通讯作者：
Marinkovich, M. Peter
中科院分区：
文献类型：
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作者：
Winge, Marten C. C.;Ohyama, Bungo;Marinkovich, M. Peter
表皮和免疫系统之间的相互作用控制着表皮组织的稳态。这些表皮-免疫相互作用在炎症性疾病牛皮癣中发生改变。然而，这种异常免疫反应背后的途径尚不清楚。在这里，我们确定 Ras 相关的 C3 肉毒毒素底物 1 (RAC1) 是表皮功能障碍的关键介质。在暴露于银屑病相关刺激的银屑病表皮和原代银屑病人角质形成细胞 (PHKC) 中，RAC1 激活持续升高，但在基底细胞癌或鳞状细胞癌患者的皮肤中则不然。小鼠中 RAC1 (RAC(V12)) 的组成型活性形式的表达导致了类似于人类牛皮癣的病变的发展，需要完整的免疫系统的存在。表达 RAC1(V12) 的小鼠和人类银屑病皮肤显示出相似的 RAC1 依赖性信号传导以及差异表达的表皮和免疫途径的转录重叠。 PHKC 与免疫细胞共培养导致 RAC1 依赖性促炎细胞因子上调，这种效应通过在正常人角质形成细胞中过度表达 RAC1 来重现。在角质形成细胞中，调节 RAC1 活性可改变分化、增殖和炎症通路，包括 STAT3、NF kappa B 和锌指蛋白 750 (ZNF750)。最后，在由人 PHKC 和免疫细胞组成的异种移植物中抑制 RAC1 可消除体内银屑病样增生和炎症。这些研究表明 RAC1 是银屑病的潜在治疗靶点，也是病理性表皮免疫相互作用的关键协调者。
Interactions between the epidermis and the immune system govern epidermal tissue homeostasis. These epidermis-immune interactions are altered in the inflammatory disease psoriasis; however, the pathways that underlie this aberrant immune response are not well understood. Here, we determined that Ras-related C3 botulinum toxin substrate 1 (RAC1) is a key mediator of epidermal dysfunction. RAC1 activation was consistently elevated in psoriatic epidermis and primary psoriatic human keratinocytes (PHKCs) exposed to psoriasis-related stimuli, but not in skin from patients with basal or squamous cell carcinoma. Expression of a constitutively active form of RAC1 (RAC(V12)) in mice resulted in the development of lesions similar to those of human psoriasis that required the presence of an intact immune system. RAC1(V12)-expressing mice and human psoriatic skin showed similar RAC1-dependent signaling as well as transcriptional overlap of differentially expressed epidermal and immune pathways. Coculture of PHKCs with immunocytes resulted in the upregulation of RAC1-dependent proinflammatory cytokines, an effect that was reproduced by overexpressing RAC1 in normal human keratinocytes. In keratinocytes, modulating RAC1 activity altered differentiation, proliferation, and inflammatory pathways, including STAT3, NF kappa B, and zinc finger protein 750 (ZNF750). Finally, RAC1 inhibition in xenografts composed of human PHKCs and immunocytes abolished psoriasiform hyperplasia and inflammation in vivo. These studies implicate RAC1 as a potential therapeutic target for psoriasis and as a key orchestrator of pathologic epidermis-immune interactions.