title: An annexin A1-FPR1 interaction contributes to necroptosis of keratinocytes in severe cutaneous adverse drug reactions.
abstract: 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.
authors.affiliation: Department of Dermatology, Hokkaido University Graduate School of Medicine, Sapporo 060-8638, Japan.
authors.forename: Nao
authors.initials: N
authors.lastname: Saito
authors.affiliation: Department of Dermatology, Hokkaido University Graduate School of Medicine, Sapporo 060-8638, Japan.
authors.forename: Hongjiang
authors.initials: H
authors.lastname: Qiao
authors.affiliation: Department of Dermatology, Hokkaido University Graduate School of Medicine, Sapporo 060-8638, Japan.
authors.forename: Teruki
authors.initials: T
authors.lastname: Yanagi
authors.affiliation: Department of Dermatology, Hokkaido University Graduate School of Medicine, Sapporo 060-8638, Japan.
authors.forename: Satoru
authors.initials: S
authors.lastname: Shinkuma
authors.affiliation: Department of Dermatology, Hokkaido University Graduate School of Medicine, Sapporo 060-8638, Japan.
authors.forename: Keiko
authors.initials: K
authors.lastname: Nishimura
authors.affiliation: Department of Dermatology, Hokkaido University Graduate School of Medicine, Sapporo 060-8638, Japan.
authors.forename: Asuka
authors.initials: A
authors.lastname: Suto
authors.affiliation: Department of Dermatology, Hokkaido University Graduate School of Medicine, Sapporo 060-8638, Japan.
authors.forename: Yasuyuki
authors.initials: Y
authors.lastname: Fujita
authors.affiliation: Department of Dermatology, Hokkaido University Graduate School of Medicine, Sapporo 060-8638, Japan.
authors.forename: Shotaro
authors.initials: S
authors.lastname: Suzuki
authors.affiliation: Department of Dermatology, Hokkaido University Graduate School of Medicine, Sapporo 060-8638, Japan.
authors.forename: Toshifumi
authors.initials: T
authors.lastname: Nomura
authors.affiliation: Department of Dermatology, Hokkaido University Graduate School of Medicine, Sapporo 060-8638, Japan.
authors.forename: Hideki
authors.initials: H
authors.lastname: Nakamura
authors.affiliation: Graduate School of Life Science, Hokkaido University, Sapporo 060-0810, Japan.
authors.forename: Koji
authors.initials: K
authors.lastname: Nagao
authors.affiliation: Graduate School of Life Science, Hokkaido University, Sapporo 060-0810, Japan.
authors.forename: Chikashi
authors.initials: C
authors.lastname: Obuse
authors.affiliation: Department of Dermatology, Hokkaido University Graduate School of Medicine, Sapporo 060-8638, Japan. aberi@med.hokudai.ac.jp shimizu@med.hokudai.ac.jp.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Shimizu
authors.affiliation: Department of Dermatology, Hokkaido University Graduate School of Medicine, Sapporo 060-8638, Japan. aberi@med.hokudai.ac.jp shimizu@med.hokudai.ac.jp.
authors.forename: Riichiro
authors.initials: R
authors.lastname: Abe
mesh_terms: D000818:Animals; D017305:Annexin A1 / Q000378:metabolism*; D017209:Apoptosis; D064007:Ataxia Telangiectasia Mutated Proteins / Q000378:metabolism; D018821:CD18 Antigens / Q000378:metabolism; D016827:CD8 Antigens / Q000378:metabolism; D004195:Disease Models, Animal; D006367:HeLa Cells; D006801:Humans; D015603:Keratinocytes / Q000378:metabolism* / Q000473:pathology* / Q000648:ultrastructure; D007963:Leukocytes, Mononuclear / Q000378:metabolism; D051379:Mice; D009336:Necrosis; D011485:Protein Binding; D012867:Skin / Q000473:pathology*; D013262:Stevens-Johnson Syndrome / Q000473:pathology / Q000628:therapy
chemical_list: D017305:Annexin A1; D018821:CD18 Antigens; D016827:CD8 Antigens; C576597:ATR protein, human; D064007:Ataxia Telangiectasia Mutated Proteins