An annexin A1-FPR1 interaction contributes to necroptosis of keratinocytes in severe cutaneous adverse drug reactions
| Autor: | Hiroshi Shimizu, Teruki Yanagi, Toshifumi Nomura, Riichiro Abe, Chikashi Obuse, Asuka Suto, Keiko Nishimura, Yasuyuki Fujita, Hongjiang Qiao, Koji Nagao, Nao Saito, Satoru Shinkuma, Hideki Nakamura, Shotaro Suzuki |
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| Rok vydání: | 2014 |
| Předmět: |
Keratinocytes
Programmed cell death Necroptosis CD8 Antigens Apoptosis Ataxia Telangiectasia Mutated Proteins Peripheral blood mononuclear cell Formyl peptide receptor 1 Mice Necrosis Annexin medicine Animals Humans Annexin A1 Skin business.industry General Medicine medicine.disease Toxic epidermal necrolysis stomatognathic diseases Disease Models Animal medicine.anatomical_structure CD18 Antigens Stevens-Johnson Syndrome Immunology Leukocytes Mononuclear Keratinocyte business HeLa Cells Protein Binding |
| Zdroj: | Science translational medicine. 6(245) |
| ISSN: | 1946-6242 |
| Popis: | Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) are life-threatening, cutaneous adverse drug reactions that are accompanied by keratinocyte cell death. Dead keratinocytes from SJS/TEN lesions exhibited necrosis, by morphological criteria. Supernatant from peripheral blood mononuclear cells (PBMCs) that had been exposed to the causative drug from patients with SJS/TEN induced the death of SJS/TEN keratinocytes, whereas supernatant from PBMCs of patients with ordinary drug skin reactions (ODSRs) exposed to the same drug did not. Keratinocytes from ODSR patients or from healthy controls were unaffected by supernatant from SJS/TEN or ODSR PBMCs. Mass spectrometric analysis identified annexin A1 as a key mediator of keratinocyte death; depletion of annexin A1 by a specific antibody diminished supernatant cytotoxicity. The necroptosis-mediating complex of RIP1 and RIP3 was indispensable for SJS/TEN supernatant-induced keratinocyte death, and SJS/TEN keratinocytes expressed abundant formyl peptide receptor 1 (FPR1), the receptor for annexin A1, whereas control keratinocytes did not. Inhibition of necroptosis completely prevented SJS/TEN-like responses in a mouse model of SJS/TEN. Our results demonstrate that a necroptosis pathway, likely mediated by annexin 1 acting through the FPR1 receptor, contributes to SJS/TEN. |
| Databáze: | OpenAIRE |
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