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

被引：64

作者：

Kinoshita, Manao ^{[1
]}

Ogawa, Youichi ^{[1
]}

Hama, Natsumi ^{[2
]}

Ujiie, Inkin ^{[3
]}

Hasegawa, Akito ^{[2
]}

Nakajima, Saeko ^{[4
]}

Nomura, Takashi ^{[4
]}

Adachi, Jun ^{[5
,6
]}

Sato, Takuya ^{[1
]}

Koizumi, Schuichi ^{[7
]}

Shimada, Shinji ^{[1
]}

Fujita, Yasuyuki ^{[3
]}

Takahashi, Hayato ^{[8
]}

Mizukawa, Yoshiko ^{[9
]}

Tomonaga, Takeshi ^{[5
,6
]}

Nagao, Keisuke ^{[10
]}

Abe, Riichiro ^{[2
]}

Kawamura, Tatsuyoshi ^{[1
]}

机构：

[1] Univ Yamanashi, Fac Med, Dept Dermatol, Kofu, Yamanashi, Japan

[2] Niigata Univ, Div Dermatol, Grad Sch Med & Dent Sci, Niigata, Japan

[3] Hokkaido Univ, Dept Dermatol, Grad Sch Med, Sapporo, Hokkaido, Japan

[4] Kyoto Univ, Dept Dermatol, Grad Sch Med, Kyoto, Japan

[5] Natl Inst Biomed Innovat Hlth & Nutr, Lab Proteome Res, Osaka, Japan

[6] Natl Inst Biomed Innovat Hlth & Nutr, Ctr Drug Design Res, Lab Prote Drug Discovery, Osaka, Japan

[7] Univ Yamanashi, Interdisciplinary Grad Sch Med, Dept Neuropharmacol, Kofu, Yamanashi, Japan

[8] Keio Univ, Dept Dermatol, Sch Med, Tokyo, Japan

[9] Kyorin Univ, Dept Dermatol, Sch Med, Tokyo, Japan

[10] Natl Inst Arthrit & Musculoskeletal & Skin Dis NI, Cutaneous Leukocyte Biol Sect, Dermatol Branch, NIH, Bethesda, MD USA

来源：

SCIENCE TRANSLATIONAL MEDICINE | 2021年 / 13卷 / 600期

关键词：

COLONY-STIMULATING FACTOR; PERIPHERAL-BLOOD NEUTROPHILS; HUMAN CATHELICIDIN LL-37; EXTRACELLULAR TRAPS; NETTING NEUTROPHILS; RECEPTOR; MIGRATION; CELLS; INTERLEUKIN-15; INVOLVEMENT;

D O I：

10.1126/scitranslmed.aax2398

中图分类号：

Q2 [细胞生物学];

学科分类号：

071009 ; 090102 ;

摘要：

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.

引用

页数：15

共 72 条

[1] Toxic epidermal necrolysis and Stevens-Johnson syndrome are induced by soluble Fas ligand [J].