2. Academic Validation
  3. Effect of opioid receptor antagonist on mitigating tumor necrosis factor-like weak inducer of apoptosis (TWEAK)-induced apoptolysis in pemphigus pathogenesis

Effect of opioid receptor antagonist on mitigating tumor necrosis factor-like weak inducer of apoptosis (TWEAK)-induced apoptolysis in pemphigus pathogenesis

  • J Autoimmun. 2024 Sep 13:149:103307. doi: 10.1016/j.jaut.2024.103307.
Xueting Peng 1,  Sijia Wang 1,  Kunyi Wu 2,  Christopher Cook 3,  Liang Li 4,  Zhao Wang 1,  Hanjiang Gu 1,  Mei Lu 1,  Guanglei Hu 1,  Kaixuan Ren 1,  Gang Hu 5,  Weihui Zeng 1,  Yumin Xia 6,  Yale Liu 7
Affiliations

Affiliations

  • 1 Department of Dermatology, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, 710004, Shaanxi, China.
  • 2 Core Research Laboratory, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, 710004, Shaanxi, China.
  • 3 Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, CA, USA.
  • 4 Department of Thoracic Surgery, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, 710004, Shaanxi, China.
  • 5 Department of Dermatology, Dermatology Hospital, Southern Medical University, Guangzhou, China.
  • 6 Department of Dermatology, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, 710004, Shaanxi, China. Electronic address: yuminxia@mail.xjtu.edu.cn.
  • 7 Department of Dermatology, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, 710004, Shaanxi, China. Electronic address: liuyale0703@xjtu.edu.cn.
PMID: 39276627 DOI: 10.1016/j.jaut.2024.103307
Abstract

Pemphigus is a severe autoimmune blistering disease characterized by acantholysis triggered by autoantibodies against desmoglein 1 and 3 (DSG1/3). Apoptosis plays a pivotal role in facilitating acantholysis, yet the precise underlying mechanism remains obscure. Tumor necrosis factor-like weak inducer of Apoptosis (TWEAK) is known to promote Apoptosis and disrupt cell junctions, although its involvement in pemphigus pathogenesis remains ambiguous. Our study observed decreased DSG1/3 expression alongside increased TWEAK/fibroblast growth factor-inducible 14 (Fn14) expression and keratinocyte Apoptosis in both lesional and perilesional skin. In vitro experiments revealed that TWEAK-stimulated keratinocytes exhibited enhanced Apoptosis, STAT1 phosphorylation, and reduced intercellular DSG1/3 expression. Notably, bulk-RNA Sequencing unveiled that Caspase-3 was responsible for mediating the DSG1/3 depletion, as confirmed by direct interaction with DSG1/3 in a co-immunoprecipitation assay. Naloxone, known for preserving cellular adhesion and preventing cell death, effectively reduced Apoptosis and restored DSG1/3 levels in TWEAK-stimulated keratinocytes. The anti-apoptotic properties of naloxone were further validated in a murine pemphigus model. Our findings elucidate that TWEAK facilitates keratinocyte Apoptosis by augmenting Caspase-3 activity, leading to DSG1/3 depletion and Apoptosis in pemphigus. Importantly, naloxone can counter TWEAK-induced Apoptosis in pemphigus pathogenesis, offering a potential therapeutic intervention.

Keywords

Desmoglein; Naloxone; Pemphigus vulgaris; STAT1; TWEAK; apoptosis.

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