Dermatology Hospital, Southern Medical University, Guangzhou, China.
Dermatology Hospital, Southern Medical University, Guangzhou, China; Cancer Research Institute, School of Basic Medical Sciences, State Key Laboratory of Organ Failure Research, National Clinical Research Center of Kidney Disease, Key Laboratory of Organ Failure Research (Ministry of Education), Southern Medical University, Guangzhou, China.
J Invest Dermatol. 2023 Jul;143(7):1208-1219.e6. doi: 10.1016/j.jid.2023.01.008. Epub 2023 Jan 28.
Keloids represent a fibrotic disorder characterized by the excessive deposition of extracellular matrix (ECM). However, the mechanisms through which ECM deposition in keloids is regulated remain elusive. In this study, we found that the expression of both TWEAK and its cognate receptor Fn14 was significantly downregulated in keloids and that TWEAK/Fn14 signaling repressed the expression of ECM-related genes in keloid fibroblasts. The IRF1 gene was essential for this repression, and the TWEAK/Fn14 downstream transcription factor p65 directly bound to the promoter of the IRF1 gene and induced its expression. Furthermore, in patients with keloid, the expression of TWEAK and Fn14 was negatively correlated with that of ECM genes and positively correlated with that of IRF1. These observations indicate that relief of TWEAK/Fn14/IRF1-mediated ECM deposition repression contributes to keloid pathogenesis, and the identified mechanism and related molecules provide potential targets for keloid treatment in the future.
瘢痕疙瘩是一种纤维组织紊乱疾病，其特征是细胞外基质（ECM）过度沉积。然而，瘢痕疙瘩中 ECM 沉积的调节机制仍不清楚。在这项研究中，我们发现 TWEAK 及其同源受体 Fn14 的表达在瘢痕疙瘩中均显著下调，TWEAK/Fn14 信号通路抑制了瘢痕疙瘩成纤维细胞中 ECM 相关基因的表达。IRF1 基因对这种抑制是必需的，TWEAK/Fn14 下游转录因子 p65 直接结合到 IRF1 基因的启动子上并诱导其表达。此外，在瘢痕疙瘩患者中，TWEAK 和 Fn14 的表达与 ECM 基因的表达呈负相关，与 IRF1 的表达呈正相关。这些观察结果表明，缓解 TWEAK/Fn14/IRF1 介导的 ECM 沉积抑制有助于瘢痕疙瘩的发病机制，所确定的机制和相关分子为未来瘢痕疙瘩的治疗提供了潜在的靶点。
