Epidermal HMGB1 Activates Dermal Fibroblasts and Causes Hypertrophic Scar Formation in Reduced Hydration
Epidermal HMGB1 Activates Dermal Fibroblasts and Causes Hypertrophic Scar Formation in Reduced Hydration
复制标题
表皮 HMGB1 激活真皮成纤维细胞并在水合作用减少时导致肥厚性疤痕形成
DOI：
10.1016/j.jid.2018.04.036
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发表时间：
2018
影响因子：
6.5
通讯作者：
Qi Shaohai
中科院分区：
文献类型：
--
作者：
Zhao Jingling;Yu Jianxing;Xu Yingbin;Chen Lei;Zhou Fei;Zhai Qiyi;Wu Jun;Shu Bin;Qi Shaohai
HMGB1蛋白是一种参与炎症反应的多功能细胞因子，已知在组织修复和纤维化中起关键作用。然而，HMGB1在纤维化皮肤病（如增生性瘢痕形成）中的功能尚不清楚。在本研究中，HMGB1在正常皮肤表皮细胞的细胞核中检测到，并在增生性疤痕的细胞质中积累。通过建立角质形成细胞-成纤维细胞共培养和条件培养基处理模型，我们发现水化条件降低会增加角质形成细胞中HMGB1的表达和分泌，从而激活真皮成纤维细胞。角质形成细胞分泌的HMGB1通过促进MRTF-A的核输入激活成纤维细胞，增加MRTF-A/SRF复合物的核积累，从而增强α -平滑肌肌动蛋白启动子的激活。此外，阻断晚期糖基化终产物或toll样受体2/4可抑制HMGB1诱导的成纤维细胞活化。最后，在兔增生性瘢痕模型中，HMGB1的局部传递导致明显的增生性瘢痕形成，而HMGB1阻断具有明显的抗瘢痕作用。我们的研究结果表明，由水合状态降低引起的高HMGB1水平在增生性瘢痕形成中起重要作用，强烈提示HMGB1是预防瘢痕形成的新靶点。
HMGB1 protein is a multifunctional cytokine involved in inflammatory reactions and is known to play a key role in tissue repair and fibrosis. However, the function of HMGB1 in fibrotic skin diseases, such as hypertrophic scar formation, remains unclear. In this study, HMGB1 was detected in the nuclei of epidermal cells in normal skin and had accumulated in the cytoplasm in hypertrophic scars. By establishing a keratinocyte-fibroblast co-culture and conditional medium treatment models, we found that a reduced hydration condition increased the expression and secretion of HMGB1 in keratinocytes, subsequently activating dermal fibroblasts. HMGB1 secreted from keratinocytes activated fibroblasts by promoting the nuclear import of MRTF-A, increased the nuclear accumulation of MRTF-A/SRF complexes and consequently enhanced α–smooth muscle actin promoter activation. Moreover, blockade of advanced glycation end products or Toll-like receptor 2/4 inhibited the fibroblast activation induced by HMGB1. Finally, local delivery of HMGB1 resulted in marked hypertrophic scar formation in rabbit hypertrophic scar models, while HMGB1 blockade exerted a clear anti-scarring effect. Our results indicate that high HMGB1 levels induced by a reduced hydration status play an important role in hypertrophic scar formation, strongly suggesting that HMGB1 is a novel target for preventing scarring.