Hosur Vishnu, Burzenski Lisa M, Stearns Timothy M, Farley Michelle L, Sundberg John P, Wiles Michael V, Shultz Leonard D
The Jackson Laboratory, Bar Harbor, ME 04609, United States.
The Jackson Laboratory, Bar Harbor, ME 04609, United States.
Exp Mol Pathol. 2017 Apr;102(2):337-346. doi: 10.1016/j.yexmp.2017.03.003. Epub 2017 Mar 6.
Rhomboid family protein RHBDF2, an upstream regulator of the epidermal growth factor (EGF) receptor signaling, has been implicated in cutaneous wound healing. However, the underlying molecular mechanisms are still emerging. In humans, a gain-of-function mutation in the RHBDF2 gene accelerates cutaneous wound healing in an EGFR-dependent manner. Likewise, a gain-of-function mutation in the mouse Rhbdf2 gene (Rhbdf2) shows a regenerative phenotype (rapid ear-hole closure) resulting from constitutive activation of the EGFR pathway. Because the RHBDF2-regulated EGFR pathway is relevant to cutaneous wound healing in humans, we used Rhbdf2 mice to investigate the biological networks and pathways leading to accelerated ear-hole closure, with the goal of identifying therapeutic targets potentially effective in promoting wound healing in humans. Comparative transcriptome analysis of ear pinna tissue from Rhbdf2 and Rhbdf2 mice at 0h, 15min, 2h, and 24h post-wounding revealed an early induction of the nuclear factor E2-related factor 2 (NRF2)-mediated anti-oxidative pathway (0h and 15min), followed by the integrin-receptor aggregation pathway (2h) as early-stage events immediately and shortly after wounding in Rhbdf2 mice. Additionally, we observed genes enriched for the Fc fragment of the IgG receptor IIIa (FCGR3A)-mediated phagocytosis pathway 24h post-wounding. Although cutaneous wound repair in healthy individuals is generally non-problematic, it can be severely impaired due to aging, diabetes, and chronic inflammation. This study suggests that activation of the NRF2-antioxidant pathway by rhomboid protein RHBDF2 might be beneficial in treating chronic non-healing wounds.
菱形家族蛋白RHBDF2是表皮生长因子（EGF）受体信号传导的上游调节因子，与皮肤伤口愈合有关。然而，其潜在的分子机制仍在不断显现。在人类中，RHBDF2基因的功能获得性突变以EGFR依赖性方式加速皮肤伤口愈合。同样，小鼠Rhbdf2基因（Rhbdf2）的功能获得性突变显示出一种再生表型（耳洞快速闭合），这是由EGFR途径的组成性激活导致的。由于RHBDF2调节的EGFR途径与人类皮肤伤口愈合相关，我们使用Rhbdf2小鼠来研究导致耳洞加速闭合的生物网络和途径，目的是确定可能有效促进人类伤口愈合的治疗靶点。对受伤后0小时、15分钟、2小时和24小时的Rhbdf2和Rhbdf2小鼠耳廓组织进行比较转录组分析，结果显示核因子E2相关因子2（NRF2）介导的抗氧化途径在早期被诱导（0小时和15分钟），随后整合素受体聚集途径（2小时）在Rhbdf2小鼠受伤后立即和不久作为早期事件出现。此外，我们观察到在受伤后24小时，IgG受体IIIa（FCGR3A）介导的吞噬途径的Fc片段相关基因富集。虽然健康个体的皮肤伤口修复通常没有问题，但由于衰老、糖尿病和慢性炎症，它可能会严重受损。这项研究表明，菱形蛋白RHBDF2激活NRF2抗氧化途径可能对治疗慢性不愈合伤口有益。
