Zhang Chen, Qiao Pei, Zhang JieYu, Luo YiXin, Xiao ChunYing, Shen ShengXian, Hasegawa Akio, Qiao HongJiang, Wang Gang, Abe Riichiro, Fu Meng
Department of Dermatology, Xijing Hospital, Fourth Military Medical University, Xi'an, China.
Division of Dermatology, Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan.
J Dermatol Sci. 2024 Dec;116(3):80-89. doi: 10.1016/j.jdermsci.2024.10.003. Epub 2024 Oct 22.
Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) are severe adverse drug reactions with extensive keratinocyte death. Carbamazepine (CBZ), the most commonly implicated drug in SJS/TEN, is metabolized by the cytochrome P450 enzyme 3A4 (CYP3A4) into carbamazepine-10,11-epoxide (CBZE) in the liver. While CD8 cytotoxic T cells play an important role in SJS/TEN, the underlying mechanism of exuberant immune response by CD8 T cells in these conditions remains incompletely understood.
To examine the expression of NLRP3 inflammasome and their skin migration in CBZE-induced SJS/TEN.
The expression of the NLRP3 inflammasome complex in skin lesions, sera, and blister fluids of SJS/TEN patients were analyzed by immunohistochemistry and enzyme-linked immunosorbent assay. NLRP3 formation and CD8 T cell activation status and their functions were examined by immunoblotting, immunofluorescence, and chemotaxis assays.
The expression of the NLRP3 inflammasome complex was greatly increased in skin lesions of SJS/TEN patients. Moreover, IL-1β and IL-18 levels in sera and blister fluids of SJS/TEN patients were approximately 3-fold higher than those in healthy individuals, with a linear correlation between IL-1β levels and disease activity. CBZE induced NLRP3 inflammasome formation, upregulated CXCL9/CXCL10 levels, and activated CD8 cytotoxic T cell functions via IL-1β/IL-1R or IL-18/IL-18R signaling in SJS/TEN keratinocytes, which promoted CD8 cytotoxic T cell migration in SJS/TEN patients.
This study showed that CBZE promoted NLRP3 inflammasome formation and strengthened the activation and function of CD8 cytotoxic T cells in the skin, which contributed to the initiation and progression of SJS/TEN.
史蒂文斯-约翰逊综合征（SJS）和中毒性表皮坏死松解症（TEN）是严重的药物不良反应，伴有广泛的角质形成细胞死亡。卡马西平（CBZ）是SJS/TEN中最常涉及的药物，在肝脏中通过细胞色素P450酶3A4（CYP3A4）代谢为卡马西平-10,11-环氧化物（CBZE）。虽然CD8细胞毒性T细胞在SJS/TEN中起重要作用，但在这些情况下CD8 T细胞过度免疫反应的潜在机制仍不完全清楚。
研究NLRP3炎性小体在CBZE诱导的SJS/TEN中的表达及其在皮肤中的迁移情况。
通过免疫组织化学和酶联免疫吸附试验分析SJS/TEN患者皮肤病变、血清和水疱液中NLRP3炎性小体复合物的表达。通过免疫印迹、免疫荧光和趋化试验检测NLRP3的形成、CD8 T细胞的活化状态及其功能。
SJS/TEN患者皮肤病变中NLRP3炎性小体复合物的表达显著增加。此外，SJS/TEN患者血清和水疱液中的IL-1β和IL-18水平比健康个体高约3倍，IL-1β水平与疾病活动度之间存在线性相关性。在SJS/TEN角质形成细胞中，CBZE通过IL-1β/IL-1R或IL-18/IL-18R信号通路诱导NLRP3炎性小体形成，上调CXCL9/CXCL10水平，并激活CD8细胞毒性T细胞功能，从而促进SJS/TEN患者CD8细胞毒性T细胞迁移。
本研究表明，CBZE促进了NLRP3炎性小体的形成，并增强了皮肤中CD8细胞毒性T细胞的活化和功能，这有助于SJS/TEN的发生和发展。
