RIKEN-IMS, Laboratory for Disease Systems Modeling, Yokohama, Japan.
RIKEN-IMS, Laboratory for Cytokine Regulation, Yokohama, Japan.
Sci Rep. 2017 Nov 20;7(1):15830. doi: 10.1038/s41598-017-16155-1.
Specific deletion of suppressor of cytokine signaling 3 (Socs3) in keratinocytes can cause severe skin inflammation with infiltration of immune cells. The molecular mechanisms and key regulatory pathways involved in these processes remain elusive. To investigate the role of Socs3 in keratinocytes, we generated and analyzed global RNA-Seq profiles from Socs3 conditional knockout (cKO) mice of two different ages (2 and 10 weeks). Over 400 genes were significantly regulated at both time points. Samples from 2-week-old mice exhibited down-regulation of genes involved in keratin-related functions and up-regulation of genes involved in lipid metabolism. At week 10, multiple chemokine and cytokine genes were up-regulated. Functional annotation revealed that the genes differentially expressed in the 2-week-old mice play roles in keratinization, keratinocyte differentiation, and epidermal cell differentiation. By contrast, differentially expressed genes in the 10-week-old animals are involved in acute immune-related functions. A group of activator protein-1-related genes were highly up-regulated in Socs3 cKO mice of both ages. This observation was validated using qRT-PCR by SOCS3-depleted human keratinocyte-derived HaCaT cells. Our results suggest that, in addition to participating in immune-mediated pathways, SOCS3 also plays important roles in skin barrier homeostasis.
特异性敲除角质形成细胞中的细胞因子信号转导抑制因子 3（SOCS3）可导致严重的皮肤炎症，伴有免疫细胞浸润。这些过程中涉及的分子机制和关键调节途径仍不清楚。为了研究 SOCS3 在角质形成细胞中的作用，我们生成并分析了来自两种不同年龄（2 周和 10 周）SOCS3 条件性敲除（cKO）小鼠的全局 RNA-Seq 图谱。在这两个时间点，超过 400 个基因受到显著调控。2 周龄小鼠的样本下调了与角蛋白相关功能相关的基因，上调了与脂质代谢相关的基因。在第 10 周时，多个趋化因子和细胞因子基因上调。功能注释表明，在 2 周龄小鼠中差异表达的基因参与角蛋白化、角质形成细胞分化和表皮细胞分化。相比之下，在 10 周龄动物中差异表达的基因与急性免疫相关功能有关。在两个年龄段的 SOCS3 cKO 小鼠中，一组激活蛋白 1 相关基因高度上调。这一观察结果通过 SOCS3 耗尽的人角质形成细胞衍生的 HaCaT 细胞的 qRT-PCR 得到了验证。我们的研究结果表明，SOCS3 除了参与免疫介导的途径外，还在皮肤屏障稳态中发挥重要作用。
