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

JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY

卷:145

Article

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, Chunying¹ 

[1] Fourth Mil Med Univ, Xijing Hosp, Dept Dermatol, 127 West Changle Rd, Xian 710032, Shaanxi, Peoples R China

[2] Southwest Med Univ Luzhou, Affiliated Hosp, Dept Dermatol, Luzhou, Peoples R China

关键词: NLR family pyrin domain containing 3 inflammasome;    vitiligo;    keratinocyte;    oxidative stress;    transient receptor potential cation channel subfamily M member 2;    calcium influx;    T-cell response;    chemokine;    cytokine;   

DOI  :  10.1016/j.jaci.2019.10.036

来源: Elsevier

【 摘 要 】

Background: 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. Objective: We sought to explicate the contribution of the activated NLRP3 inflammasome in keratinocytes to the autoimmune response in patients with vitiligo. Methods: 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. Results: Expressions of NLRP3 and downstream cytokine IL-1 beta were consistently increased in perilesional keratinocytes of patients with vitiligo. Notably, serum IL-1 beta 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 CD81(+) T cells and inhibited the production of cytokines in T cells in patients with vitiligo. Conclusion: Oxidative stress-induced NLRP3 inflammasome activation in keratinocytes promotes the cutaneous T-cell response, which could be targeted for the treatment of vitiligo.

【 授权许可】

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