Boyko Tatiana V, Bam Rakesh, Jiang Dadi, Wang Zhen, Bhatia Namrata, Tran Misha C, Longaker Michael T, Koong Albert C, Yang George P
Department of Surgery, Stanford University School of Medicine, Stanford, California.
Department of Surgery, University at Buffalo, SSUNY, Buffalo, New York.
Wound Repair Regen. 2017 Nov;25(6):964-971. doi: 10.1111/wrr.12603. Epub 2018 Feb 6.
Wound healing is characterized by the production of large amounts of protein necessary to replace lost cellular mass and extracellular matrix. The unfolded protein response (UPR) is an important adaptive cellular response to increased protein synthesis. One of the main components of the UPR is IRE1, an endoplasmic reticulum transmembrane protein with endonuclease activity that produces the activated form of the transcription factor XBP1. Using luciferase reporter mice for Xbp1 splicing, we showed that IRE1 was up-regulated during excisional wound healing at the time in wound healing consistent with that of the proliferative phase, when the majority of protein synthesis for cellular proliferation and matrix deposition occurs. Furthermore, using a small molecule inhibitor of IRE1 we demonstrated that inhibition of IRE1 led to decreased scar formation in treated mice. Results were recapitulated in a hypertrophic scar mouse model. These data help provide a cellular pathway to target in the treatment of hypertrophic scarring and keloid disorders.
伤口愈合的特征是产生大量蛋白质，以替代丢失的细胞物质和细胞外基质。未折叠蛋白反应（UPR）是细胞对蛋白质合成增加的一种重要适应性反应。UPR的主要成分之一是IRE1，它是一种具有核酸内切酶活性的内质网跨膜蛋白，可产生转录因子XBP1的活化形式。利用Xbp1剪接的荧光素酶报告基因小鼠，我们发现IRE1在切除伤口愈合过程中，在与增殖期一致的伤口愈合时间上调，此时细胞增殖和基质沉积的大部分蛋白质合成发生。此外，使用IRE1的小分子抑制剂，我们证明抑制IRE1可导致治疗小鼠的瘢痕形成减少。在肥厚性瘢痕小鼠模型中也得到了类似的结果。这些数据有助于提供一条在治疗肥厚性瘢痕和瘢痕疙瘩疾病时可靶向的细胞途径。
