Genome-Wide Transcriptional Profiling of Skin and Dorsal Root Ganglia after Ultraviolet-B-Induced Inflammation

Ultraviolet-B (UVB)-induced inflammation produces a dose-dependent mechanical and thermal hyperalgesia in both humans and rats, most likely via inflammatory mediators acting at the site of injury. Previous work has shown that the gene expression of cytokines and chemokines is positively correlated between species and that these factors can contribute to UVB-induced pain. In order to investigate other potential pain mediators in this model we used RNA-seq to perform genome-wide transcriptional profiling in both human and rat skin at the peak of hyperalgesia. In addition we have also measured transcriptional changes in the L4 and L5 DRG of the rat model. Our data show that UVB irradiation produces a large number of transcriptional changes in the skin: 2186 and 3888 genes are significantly dysregulated in human and rat skin, respectively. The most highly up-regulated genes in human skin feature those encoding cytokines (IL6 and IL24), chemokines (CCL3, CCL20, CXCL1, CXCL2, CXCL3 and CXCL5), the prostanoid synthesising enzyme COX-2 and members of the keratin gene family. Overall there was a strong positive and significant correlation in gene expression between the human and rat (R = 0.8022). In contrast to the skin, only 39 genes were significantly dysregulated in the rat L4 and L5 DRGs, the majority of which had small fold change values. Amongst the most up-regulated genes in DRG were REG3B, CCL2 and VGF. Overall, our data shows that numerous genes were up-regulated in UVB irradiated skin at the peak of hyperalgesia in both human and rats. Many of the top up-regulated genes were cytokines and chemokines, highlighting again their potential as pain mediators. However many other genes were also up-regulated and might play a role in UVB-induced hyperalgesia. In addition, the strong gene expression correlation between species re-emphasises the value of the UVB model as translational tool to study inflammatory pain.紫外线B（Ultraviolet-B，UVB）诱导的炎症可在人类与大鼠体内引发剂量依赖性的机械痛觉超敏与热痛觉超敏，其潜在机制大概率为炎症介质作用于损伤局部。既往研究表明，不同物种间细胞因子（cytokines）与趋化因子（chemokines）的基因表达呈显著正相关，且此类因子可参与UVB诱导的疼痛过程。为探究该模型中其他潜在疼痛介质，我们采用RNA测序（RNA-seq）对痛觉超敏峰值期的人类与大鼠皮肤进行了全基因组转录谱分析。此外，我们还对大鼠模型的L4与L5背根神经节（Dorsal Root Ganglion, DRG）的转录变化进行了检测。我们的研究数据显示，UVB照射可引发皮肤内大量转录组变化：人类与大鼠皮肤中分别有2186个和3888个基因发生显著差异表达。人类皮肤中上调幅度最高的基因包括编码细胞因子（IL6、IL24）、趋化因子（CCL3、CCL20、CXCL1、CXCL2、CXCL3及CXCL5）的基因，前列腺素合成酶环氧合酶-2（Cyclooxygenase-2，COX-2），以及角蛋白基因家族成员。总体而言，人类与大鼠的基因表达呈现出极强且显著的正相关（R=0.8022）。与皮肤形成鲜明对比的是，大鼠L4、L5背根神经节中仅有39个基因发生显著差异表达，其中大多数的差异倍数较小。背根神经节中上调幅度最高的基因包括REG3B、CCL2与VGF。综上，我们的数据表明，在痛觉超敏峰值期，UVB照射可使人类与大鼠皮肤内大量基因出现上调表达；其中众多排名靠前的上调基因为细胞因子与趋化因子，再次凸显了此类因子作为疼痛介质的潜在价值。不过，还有众多其他基因也发生了上调表达，可能在UVB诱导的痛觉超敏过程中发挥作用。此外，不同物种间极强的基因表达相关性再次证实，UVB模型可作为研究炎症性疼痛的有效转化研究工具。