Research ArticleSKIN

Neutrophils initiate and exacerbate Stevens-Johnson syndrome and toxic epidermal necrolysis

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Science Translational Medicine  30 Jun 2021:
Vol. 13, Issue 600, eaax2398
DOI: 10.1126/scitranslmed.aax2398

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Skin-deep drug reactions

Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) are similar life-threatening forms of severe cutaneous adverse drug reactions that have a spectrum of symptoms and few treatment options. Kinoshita et al. gained insight into the pathological immune responses associated with SJS/TEN by analyzing skin and blister fluid samples from patients. They identified skin-infiltrating CD8+ T cells that produced lipocalin-2 in response to drug exposure and induced neutrophil extracellular trap formation (NETosis). NETosis triggered the release of the antimicrobial peptide LL-37 and expression of formyl peptide receptor 1 (FPR1) in keratinocytes, which caused necroptosis. The NETosis-necroptosis axis was specific to SJS/TEN, and these findings provide immunological insights that may be used toward the development of new therapies for cADR.

Abstract

Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (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, which 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.

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