[Research Articles] Neutrophils initiate and exacerbate Stevens-Johnson syndrome and toxic epidermal necrolysis

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.

Source: Science Translational Medicine - June 30, 2021 Category: Biomedical Science Authors: Kinoshita, M., Ogawa, Y., Hama, N., Ujiie, I., Hasegawa, A., Nakajima, S., Nomura, T., Adachi, J., Sato, T., Koizumi, S., Shimada, S., Fujita, Y., Takahashi, H., Mizukawa, Y., Tomonaga, T., Nagao, K., Abe, R., Kawamura, T. Tags: Research Articles Source Type: research