Abstract：
TRPV3 is a temperature-sensitive calcium-permeable channel. In previous studies, we noticed prominent TUNEL-positive keratinocytes in patients with Olmsted syndrome and Trpv3+/G568V mice, both of which carry gain-of-function variants in the TRPV3 gene. However, it remains unclear how the keratinocytes die and whether this process contributes to more skin disorders. In this study, we showed that gain-of-function variant or pharmacological activation of TRPV3 resulted in poly(ADP-ribose) polymerase 1 (PARP1)/AIFM1/macrophage migration inhibitory factor axis-mediated parthanatos, which is an underestimated form of cell death in skin diseases. Chelating calcium, scavenging ROS, or inhibiting nitric oxide synthase effectively rescued the parthanatos, indicating that TRPV3 regulates parthanatos through calcium-mediated oxidative stress. Furthermore, inhibiting PARP1 downregulated TSLP and IL33 induced by TRPV3 activation in HaCaT cells, reduced immune cell infiltration, and ameliorated epidermal thickening in Trpv3+/G568V mice. Marked parthanatos was also detected in the skin of MC903-treated mice and patients with atopic dermatitis, whereas inhibiting PARP1 largely alleviated the MC903-induced dermatitis. In addition, stimulating parthanatos in mouse skin with methylnitronitrosoguanidine recapitulated many features of atopic dermatitis. These data demonstrate that the TRPV3-regulated parthanatos-associated PARP1/AIFM1/macrophage migration inhibitory factor axis is a critical contributor to the pathogenesis of Olmsted syndrome and atopic dermatitis, suggesting that modulating the PARP1/AIFM1/macrophage migration inhibitory factor axis is a promising therapy for these conditions.
摘要：
TRPV3是温度敏感的钙渗透通道。在以往的研究中,我们注意到在Olmsted综合征患者和Trpv3+/G568V小鼠中突出的TUNEL阳性角质形成细胞,两者都在TRPV3基因中携带功能获得突变。然而,目前尚不清楚角质形成细胞是如何死亡的，以及这一过程是否会导致更多的皮肤疾病。在这里，我们表明，TRPV3的功能获得突变或药理激活导致PARP1/AIFM1/MIF轴介导的parthanatos，这是皮肤病中一种被低估的细胞死亡形式。螯合钙，清除活性氧或抑制一氧化氮合酶有效地拯救了parthanatos，表明TRPV3通过钙介导的氧化应激调节parthanatos。此外，抑制PARP1下调由TRPV3活化诱导的HaCaT细胞中的TSLP和IL33，减少免疫细胞浸润，并改善Trpv3+/G568V小鼠的表皮增厚。在MC903治疗的小鼠和特应性皮炎（AD）患者的皮肤中也检测到标记的parthanatos，而抑制PARP1在很大程度上缓解了MC903诱导的皮炎。此外,用甲基硝基亚硝基胍刺激小鼠皮肤中的parthanatos，概括了AD的许多特征。这些数据表明，TRPV3调节的parthanatos相关PARP1/AIFM1/MIF轴是Olmsted综合征和AD发病机理的关键贡献者，提示调节PARP1/AIFM1/MIF轴是治疗这些疾病的有希望的治疗方法。
