Activated NLR family pyrin domain containing 3 (NLRP3) inflammasome in keratinocytes promotes cutaneous T-cell response in patients with vitiligo
Activated NLR family pyrin domain containing 3 (NLRP3) inflammasome in keratinocytes promotes cutaneous T-cell response in patients with vitiligo
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角质形成细胞中激活的 NLR 家族含热蛋白结构域 3 (NLRP3) 炎性体促进白癜风患者的皮肤 T 细胞反应
DOI：
10.1016/j.jaci.2019.10.036
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发表时间：
2020-02-01
影响因子：
14.2
通讯作者：
Li, Chunying
中科院分区：
文献类型：
--
作者：
Li, Shuli;Kang, Pan;Li, Chunying
背景资料：角质形成细胞可以在氧化应激下作为先天免疫细胞发挥作用，并加剧皮肤T细胞反应，从而破坏白癜风背景下的黑素细胞。NOD样受体家族pyrin domain containing 3（NLRP 3）炎性体是存在于角质形成细胞中的先天免疫的调节剂。然而，NLRP 3炎性小体在白癜风发病机制中的作用还没有被investigated.Objective：我们试图阐明角质形成细胞中活化的NLRP 3炎性小体对白癜风患者自身免疫应答的贡献。用H2 O2处理培养的角质形成细胞，以研究氧化应激下NLRP 3炎性小体活化的机制。结果：白癜风患者皮损周围角质形成细胞中NLRP 3及其下游细胞因子IL-1 β的表达持续增高，而皮损周围角质形成细胞中NLRP 3的表达则明显增高。值得注意的是，白癜风患者血清IL-1 β水平升高，与疾病活动和严重程度相关，有效治疗后下降。此外，氧化应激通过瞬时受体电位阳离子通道亚家族M成员2（TRPM 2）促进角质形成细胞中NLRP 3炎性小体活化，TRPM 2是一种氧化还原敏感性阳离子通道，其依赖于TRPM 2介导的钙内流。结论：氧化应激诱导的角质形成细胞NLRP 3炎性小体激活促进皮肤T细胞反应，可能成为治疗白癜风的靶点。
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.