Institute of Genomic Medicine, Wenzhou Medical University, Wenzhou, China; Dermatology and Venereology Division, Department of Medicine (Solna), Karolinska Institute, Stockholm, Sweden.
Dermatology and Venereology Division, Department of Medicine (Solna), Karolinska Institute, Stockholm, Sweden.
J Invest Dermatol. 2020 Feb;140(2):465-476.e11. doi: 10.1016/j.jid.2019.07.694. Epub 2019 Jul 31.
Venous ulcers are the most common type of human chronic nonhealing wounds and are stalled in a constant and excessive inflammatory state. The molecular mechanisms underlying the chronic wound inflammation remain elusive. Moreover, little is known about the role of regulatory RNAs, such as microRNAs, in the pathogenesis of venous ulcers. We found that both microRNA (miR)-34a and miR-34c were upregulated in the wound-edge epidermal keratinocytes of venous ulcers compared with normal wounds or the skin. In keratinocytes, miR-34a and miR-34c promoted inflammatory chemokine and cytokine production. In wounds of wild-type mice, miR-34a-mimic treatment enhanced inflammation and delayed healing. To further explore how miR-34 functions, LGR4 was identified as a direct target mediating the proinflammatory function of miR-34a and miR-34c. Interestingly, impaired wound closure with enhanced inflammation was also observed in Lgr4 knockout mice. Mechanistically, the miR-34-LGR4 axis regulated GSK-3β-induced p65 serine 468 phosphorylation, changing the activity of the NF-κB signaling pathway. Collectively, the miR-34-LGR4 axis was shown to regulate keratinocyte inflammatory response, the deregulation of which may play a pathological role in venous ulcers.
静脉溃疡是最常见的人类慢性难愈性创面，处于持续且过度的炎症状态。慢性创面炎症的分子机制仍难以捉摸。此外，关于调节 RNA（如 microRNA）在静脉溃疡发病机制中的作用知之甚少。我们发现，与正常伤口或皮肤相比，静脉溃疡创缘表皮角质形成细胞中 microRNA (miR)-34a 和 miR-34c 均上调。在角质形成细胞中，miR-34a 和 miR-34c 促进炎症趋化因子和细胞因子的产生。在野生型小鼠的伤口中，miR-34a 模拟物治疗增强了炎症并延迟了愈合。为了进一步探索 miR-34 的作用机制，鉴定出 LGR4 是介导 miR-34a 和 miR-34c 促炎功能的直接靶标。有趣的是，Lgr4 基因敲除小鼠也观察到伤口闭合受损伴炎症增强。从机制上讲，miR-34-LGR4 轴调节 GSK-3β 诱导的 p65 丝氨酸 468 磷酸化，改变 NF-κB 信号通路的活性。总之，miR-34-LGR4 轴调节角质形成细胞的炎症反应，其失调可能在静脉溃疡中发挥病理性作用。
