Neutrophils initiate and exacerbate Stevens-Johnson syndrome and toxic epidermal necrolysis.
Neutrophils initiate and exacerbate Stevens-Johnson syndrome and toxic epidermal necrolysis.
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DOI：
10.1126/scitranslmed.aax2398
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发表时间：
2021-06-30
影响因子：
17.1
通讯作者：
中科院分区：
文献类型：
--
作者：
Stevens-Johnson综合征/中毒性表皮坏死松解症（SJS/TEN）是以大量表皮脱离为特征的危及生命的皮肤粘膜药物不良反应。已知细胞毒性T细胞和相关效应分子驱动SJS/TEN病理生理学，但先天性免疫应答的贡献尚不清楚。我们描述了中性粒细胞在SJS/TEN早期阶段触发炎症的机制。皮肤浸润性CD 8 + T细胞以药物特异性方式产生脂质运载蛋白-2，其触发了早期病变皮肤中中性粒细胞胞外陷阱（NET）的形成。经历NETosis的中性粒细胞释放LL-37，一种抗菌肽，其诱导角质形成细胞的甲酰肽受体1（FPR 1）表达。FPR 1表达导致角质形成细胞易受坏死性凋亡的影响，这导致坏死性凋亡角质形成细胞进一步释放LL-37，并诱导周围角质形成细胞上的FPR 1表达，可能放大了坏死性凋亡反应。在不太严重的皮肤药物不良反应、自身免疫性疾病或嗜中性粒细胞相关疾病中未观察到NETs-坏死性凋亡轴，表明这是SJS/TEN特有的过程。SJS/TEN角质形成细胞坏死性凋亡的发生和进展似乎涉及由先天性和适应性免疫应答介导的级联事件，了解这些应答可能有助于识别这些药物不良反应的诊断标志物或治疗靶点。由药物特异性CD 8 + T细胞诱导的神经细胞外陷阱启动SJS/TEN。
Stevens–Johnson syndrome/toxic epidermal necrolysis (SJS/TEN) are life-threatening mucocutaneous adverse drug reactions characterized by massive epidermal detachment. Cytotoxic T cells and associated effector molecules are known to drive SJS/TEN pathophysiology, but the contribution of innate immune responses is not well understood. We describe a mechanism by which neutrophils triggered inflammation during early phases of SJS/TEN. Skin-infiltrating CD8+ T cells produced lipocalin-2 in a drug-specific manner, which triggered the formation of neutrophil extracellular traps (NETs) in early lesional skin. Neutrophils undergoing NETosis released LL-37, an antimicrobial peptide, which induced formyl peptide receptor 1 (FPR1) expression by keratinocytes. FPR1 expression caused keratinocytes to be vulnerable to necroptosis that caused further release of LL-37 by necroptotic keratinocytes and induced FPR1 expression on surrounding keratinocytes, likely amplified the necroptotic response. The NETs-necroptosis axis was not observed in less severe cutaneous adverse drug reactions, autoimmune diseases, or neutrophil-associated disorders, suggesting that this was a process specific to SJS/TEN. Initiation and progression of SJS/TEN keratinocyte necroptosis appear to involve a cascade of events mediated by innate and adaptive immune responses, and understanding these responses may contribute to the identification of diagnostic markers or therapeutic targets for these adverse drug reactions. Neutrophil extracellular traps induced by drug-specific CD8+ T cells initiate SJS/TEN.
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影响因子：
4.6
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通讯作者：
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