2. Academic Validation
  3. TRPV3-Activated PARP1/AIFM1/MIF Axis through Oxidative Stress Contributes to Atopic Dermatitis

TRPV3-Activated PARP1/AIFM1/MIF Axis through Oxidative Stress Contributes to Atopic Dermatitis

  • J Invest Dermatol. 2024 May 30:S0022-202X(24)00384-1. doi: 10.1016/j.jid.2024.04.020.
Zhongya Song 1,  Meng Gao 1,  Tianxiao Li 1,  Yi Zhang 2,  Zhiming Chen 3,  Linghan Hu 1,  Juan Liu 4,  Yingshi Li 1,  Xi Wang 1,  Yihe Liu 1,  Ran Mo 1,  Ruiyu Xiang 1,  Di Hua 1,  Hao Chen 5,  Ming Zhao 6,  Xu Chen 6,  Xu Yao 7,  Yong Yang 8
Affiliations

Affiliations

  • 1 Genetic Skin Disease Center, Hospital for Skin Diseases, Institute of Dermatology, Chinese Academy of Medical Sciences & Peking Union Medical College, Nanjing, China.
  • 2 Department of Plastic and Reconstructive Surgery, Hospital for Skin Diseases, Institute of Dermatology, Chinese Academy of Medical Sciences & Peking Union Medical College, Nanjing, China.
  • 3 Genetic Skin Disease Center, Hospital for Skin Diseases, Institute of Dermatology, Chinese Academy of Medical Sciences & Peking Union Medical College, Nanjing, China; Jiangsu Key Laboratory of Molecular Biology for Skin Diseases and STIs, Hospital for Skin Diseases, Institute of Dermatology, Chinese Academy of Medical Sciences & Peking Union Medical College, Nanjing, China.
  • 4 Department of Dermatology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China.
  • 5 Department of Pathology, Hospital for Skin Diseases, Institute of Dermatology, Chinese Academy of Medical Sciences & Peking Union Medical College, Nanjing, China.
  • 6 Key Laboratory of Basic and Translational Research on Immune-Mediated Skin Diseases, Hospital for Skin Diseases, Institute of Dermatology, Chinese Academy of Medical Sciences & Peking Union Medical College, Nanjing, China.
  • 7 Department of Allergy and Rheumatology, Hospital for Skin Diseases, Institute of Dermatology, Chinese Academy of Medical Sciences & Peking Union Medical College, Nanjing, China.
  • 8 Genetic Skin Disease Center, Hospital for Skin Diseases, Institute of Dermatology, Chinese Academy of Medical Sciences & Peking Union Medical College, Nanjing, China; Jiangsu Key Laboratory of Molecular Biology for Skin Diseases and STIs, Hospital for Skin Diseases, Institute of Dermatology, Chinese Academy of Medical Sciences & Peking Union Medical College, Nanjing, China. Electronic address: yyang@pumcderm.cams.cn.
PMID: 38823435 DOI: 10.1016/j.jid.2024.04.020
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.

Keywords

Atopic dermatitis; Olmsted syndrome; Oxidative stress; Parthanatos; TRPV3.

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