2. Academic Validation
  3. Targeting TRPV1-mediated autophagy attenuates nitrogen mustard-induced dermal toxicity

Targeting TRPV1-mediated autophagy attenuates nitrogen mustard-induced dermal toxicity

  • Signal Transduct Target Ther. 2021 Jan 25;6(1):29. doi: 10.1038/s41392-020-00389-z.
Mingliang Chen # 1 2 3,  Xunhu Dong # 1 3,  Haoyue Deng # 4,  Feng Ye 1 3,  Yuanpeng Zhao 1 3,  Jin Cheng 1 3,  Guorong Dan 1 3,  Jiqing Zhao 1 3,  Yan Sai 1 3,  Xiuwu Bian 5,  Zhongmin Zou 6 7
Affiliations

Affiliations

  • 1 Department of Chemical Defense Medicine, School of Military Preventive Medicine, Third Military Medical University (Army Medical University), 30 Gaotanyan Street, Shapingba District, Chongqing, 400038, China.
  • 2 Institute of Pathology and Southwest Cancer Centre, Southwest Hospital, Third Military Medical University (Army Medical University), Chongqing, 400038, China.
  • 3 Institute of Toxicology, School of Military Preventive Medicine, Third Military Medical University (Army Medical University), 30 Gaotanyan Street, Shapingba District, Chongqing, 400038, China.
  • 4 State Key Laboratory of Trauma, Burns and Combined Injury, Second Department of Research Institute of Surgery, Daping Hospital, Third Military Medical University (Army Medical University), Chongqing, 400042, China.
  • 5 Institute of Pathology and Southwest Cancer Centre, Southwest Hospital, Third Military Medical University (Army Medical University), Chongqing, 400038, China. [email protected].
  • 6 Department of Chemical Defense Medicine, School of Military Preventive Medicine, Third Military Medical University (Army Medical University), 30 Gaotanyan Street, Shapingba District, Chongqing, 400038, China. [email protected].
  • 7 Institute of Toxicology, School of Military Preventive Medicine, Third Military Medical University (Army Medical University), 30 Gaotanyan Street, Shapingba District, Chongqing, 400038, China. [email protected].
  • # Contributed equally.
PMID: 33487631 DOI: 10.1038/s41392-020-00389-z
Abstract

Nitrogen mustard (NM) causes severe vesicating skin injury, which lacks effective targeted therapies. The major limitation is that the specific mechanism of NM-induced skin injury is not well understood. Recently, Autophagy has been found to play important roles in physical and chemical exposure-caused cutaneous injuries. However, whether Autophagy contributes to NM-induced dermal toxicity is unclear. Herein, we initially confirmed that NM dose-dependently caused cell death and induced Autophagy in keratinocytes. Suppression of Autophagy by 3-methyladenine, chloroquine, and bafilomycin A1 or ATG5 siRNA attenuated NM-induced keratinocyte cell death. Furthermore, NM increased transient receptor potential vanilloid 1 (TRPV1) expression, intracellular CA2+ content, and the activities of CA2+/calmodulin-dependent kinase kinase β (CaMKKβ), AMP-activated protein kinase (AMPK), unc-51-like kinase 1 (ULK1), and mammalian target of rapamycin (mTOR). NM-induced Autophagy in keratinocytes was abolished by treatment with inhibitors of TRPV1 (capsazepine), CaMKKβ (STO-609), AMPK (compound C), and ULK1 (SBI-0206965) as well as TRPV1, CaMKKβ, and AMPK siRNA transfection. In addition, an mTOR Inhibitor (rapamycin) had no significant effect on NM-stimulated Autophagy or cell death of keratinocytes. Finally, the results of the in vivo experiment in NM-treated skin tissues were consistent with the findings of the in vitro experiment. In conclusion, NM-caused dermal toxicity by overactivating Autophagy partially through the activation of TRPV1-Ca2+-CaMKKβ-AMPK-ULK1 signaling pathway. These results suggest that blocking TRPV1-dependent Autophagy could be a potential treatment strategy for NM-caused cutaneous injury.

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