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Activated NLR family pyrin domain containing 3 (NLRP3) inflammasome in keratinocytes promotes cutaneous T-cell response in patients with vitiligo.

Authors
  • Li, Shuli1
  • Kang, Pan1
  • Zhang, Weigang1
  • Jian, Zhe1
  • Zhang, Qian1
  • Yi, Xiuli1
  • Guo, Sen1
  • Guo, Weinan1
  • Shi, Qiong1
  • Li, Bing1
  • He, Yuanmin2
  • Song, Pu1
  • Liu, Ling1
  • Li, Kai1
  • Wang, Gang1
  • Gao, Tianwen1
  • Li, Chunying3
  • 1 Department of Dermatology, Xijing Hospital, Fourth Military Medical University, Xi'an, China. , (China)
  • 2 Department of Dermatology, Affiliated Hospital of Southwest Medical University, Luzhou, China. , (China)
  • 3 Department of Dermatology, Xijing Hospital, Fourth Military Medical University, Xi'an, China. Electronic address: [email protected] , (China)
Type
Published Article
Journal
The Journal of allergy and clinical immunology
Publication Date
Feb 01, 2020
Volume
145
Issue
2
Pages
632–645
Identifiers
DOI: 10.1016/j.jaci.2019.10.036
PMID: 31756352
Source
Medline
Keywords
Language
English
License
Unknown

Abstract

Keratinocytes can function as innate immune cells under oxidative stress and aggravate the cutaneous T-cell response that undermines melanocytes in the setting of vitiligo. The NOD-like receptor family pyrin domain containing 3 (NLRP3) inflammasome is a regulator of innate immunity that exists in keratinocytes. However, the role of the NLRP3 inflammasome in the pathogenesis of vitiligo has not been investigated. We sought to explicate the contribution of the activated NLRP3 inflammasome in keratinocytes to the autoimmune response in patients with vitiligo. Perilesional and serum samples from patients with vitiligo were collected to examine the status of the NLRP3 inflammasome in the setting of vitiligo. Cultured keratinocytes were treated with H2O2 to investigate the mechanism for NLRP3 inflammasome activation under oxidative stress. Peripheral blood T cells were extracted from patients with vitiligo to explore the influence of the NLRP3 inflammasome on the T-cell response in patients with vitiligo. Expressions of NLRP3 and downstream cytokine IL-1β were consistently increased in perilesional keratinocytes of patients with vitiligo. Notably, serum IL-1β levels were increased in patients with vitiligo, correlated with disease activity and severity, and decreased after effective therapy. Furthermore, oxidative stress promoted NLRP3 inflammasome activation in keratinocytes through transient receptor potential cation channel subfamily M member 2 (TRPM2), a redox-sensitive cation channel, which was dependent on TRPM2-mediated calcium influx. More importantly, blocking TRPM2-induced NLRP3 inflammasome activation in keratinocytes impaired chemotaxis for CD8+ T cells and inhibited the production of cytokines in T cells in patients with vitiligo. Oxidative stress-induced NLRP3 inflammasome activation in keratinocytes promotes the cutaneous T-cell response, which could be targeted for the treatment of vitiligo. Copyright © 2019 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.

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