Biomedical Institute, BRIC, University of Copenhagen, Ole Maaløes Vej 5, 2200 Copenhagen, Denmark.
J Cell Sci. 2012 Nov 15;125(Pt 22):5379-90. doi: 10.1242/jcs.107011. Epub 2012 Sep 6.
Crosstalk between keratinocytes and immune cells is crucial for the immunological barrier function of the skin, and aberrant crosstalk contributes to inflammatory skin diseases. Using mice with a keratinocyte-restricted deletion of the RAC1 gene we found that RAC1 in keratinocytes plays an important role in modulating the interferon (IFN) response in skin. These RAC1 mutant mice showed increased sensitivity in an irritant contact dermatitis model, abnormal keratinocyte differentiation, and increased expression of immune response genes including the IFN signal transducer STAT1. Loss of RAC1 in keratinocytes decreased actin polymerization in vivo and in vitro and caused Arp2/3-dependent expression of STAT1, increased interferon sensitivity and upregulation of aberrant keratinocyte differentiation markers. This can be inhibited by the AP-1 inhibitor tanshinone IIA. Loss of RAC1 makes keratinocytes hypersensitive to inflammatory stimuli both in vitro and in vivo, suggesting a major role for RAC1 in regulating the crosstalk between the epidermis and the immune system.
角质形成细胞与免疫细胞之间的串扰对于皮肤的免疫屏障功能至关重要，异常的串扰会导致炎症性皮肤病。使用角质形成细胞中 RAC1 基因特异性缺失的小鼠，我们发现角质形成细胞中的 RAC1 在调节皮肤中的干扰素（IFN）反应中发挥重要作用。这些 RAC1 突变小鼠在刺激性接触性皮炎模型中表现出更高的敏感性，角质形成细胞分化异常，以及包括 IFN 信号转导子 STAT1 在内的免疫反应基因的表达增加。角质形成细胞中 RAC1 的缺失减少了体内和体外的肌动蛋白聚合，并导致 Arp2/3 依赖性 STAT1 表达增加、干扰素敏感性增加和异常角质形成细胞分化标志物的上调。这可以被 AP-1 抑制剂丹参酮 IIA 抑制。RAC1 的缺失使角质形成细胞在体外和体内对炎症刺激更加敏感，这表明 RAC1 在调节表皮和免疫系统之间的串扰中起着重要作用。
