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

• Published in: Science translational medicine Vol. 13; no. 600
• Main Authors: Kinoshita, Manao, Ogawa, Youichi, Hama, Natsumi, Ujiie, Inkin, Hasegawa, Akito, Nakajima, Saeko, Nomura, Takashi, Adachi, Jun, Sato, Takuya, Koizumi, Schuichi, Shimada, Shinji, Fujita, Yasuyuki, Takahashi, Hayato, Mizukawa, Yoshiko, Tomonaga, Takeshi, Nagao, Keisuke, Abe, Riichiro, Kawamura, Tatsuyoshi
• Format: Journal Article
• Language: English
• Published: United States 30.06.2021
• Subjects: CD8-Positive T-Lymphocytes; Humans; Keratinocytes; Neutrophils; Stevens-Johnson Syndrome; T-Lymphocytes, Cytotoxic
• ISSN: 1946-6242
• DOI: 10.1126/scitranslmed.aax2398

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.