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

Manao Kinoshita, Youichi Ogawa, Natsumi Hama, Inkin Ujiie, Akito Hasegawa, Saeko Nakajima, Takashi Nomura, Jun Adachi, Takuya Sato, Schuichi Koizumi, Shinji Shimada, Yasuyuki Fujita, Hayato Takahashi, Yoshiko Mizukawa, Takeshi Tomonaga, Keisuke Nagao, Riichiro Abe, Tatsuyoshi Kawamura

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish
Article numbereaax2398
JournalScience translational medicine
Volume13
Issue number600
DOIs
Publication statusPublished - 2021 Jun 30

ASJC Scopus subject areas

  • Medicine(all)

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