Hansjörg Wyss Department of Plastic Surgery, NYU Langone Health, New York, NY 10016, USA.
Rutgers Robert Wood Johnson School of Medicine, New Jersey, NJ 08854, USA.
Cell Rep. 2020 Nov 24;33(8):108417. doi: 10.1016/j.celrep.2020.108417.
Unveiling the molecular mechanisms underlying tissue regeneration provides new opportunities to develop treatments for diabetic ulcers and other chronic skin lesions. Here, we show that Ccl2 secretion by epidermal keratinocytes is directly orchestrated by Nrf2, a prominent transcriptional regulator of tissue regeneration that is activated early after cutaneous injury. Through a unique feedback mechanism, we find that Ccl2 from epidermal keratinocytes not only drives chemotaxis of macrophages into the wound but also triggers macrophage expression of EGF, which in turn activates basal epidermal keratinocyte proliferation. Notably, we find dysfunctional activation of Nrf2 in epidermal keratinocytes of diabetic mice after wounding, which partly explains regenerative impairments associated with diabetes. These findings provide mechanistic insight into the critical relationship between keratinocyte and macrophage signaling during tissue repair, providing the basis for continued investigation of the therapeutic value of Nrf2.
揭示组织再生的分子机制为治疗糖尿病性溃疡和其他慢性皮肤损伤提供了新的机会。在这里，我们表明表皮角质形成细胞中 Ccl2 的分泌是由 Nrf2 直接调控的，Nrf2 是组织再生的主要转录调节剂，在皮肤损伤后早期被激活。通过一个独特的反馈机制，我们发现表皮角质形成细胞中的 Ccl2 不仅驱动巨噬细胞向伤口趋化，还触发巨噬细胞表达 EGF，进而激活基底表皮角质形成细胞增殖。值得注意的是，我们发现糖尿病小鼠在受伤后表皮角质形成细胞中 Nrf2 的功能激活异常，这部分解释了与糖尿病相关的再生障碍。这些发现为角质形成细胞和巨噬细胞信号在组织修复过程中的关键关系提供了机制上的见解，为进一步研究 Nrf2 的治疗价值提供了基础。
