TNF‐α induced extracellular release of keratinocyte high‐mobility group box 1 in Stevens‐Johnson syndrome/toxic epidermal necrolysis: Biomarker and putative mechanism of pathogenesis

Decreased epidermal high‐mobility group box 1 (HMGB1) expression is an early marker of epidermal injury in Stevens–Johnson syndrome/toxic epidermal necrolysis (SJS/TEN). Etanercept, an anti‐tumor necrosis factor therapeutic, is effective in the treatment of SJS/TEN. The objective was to characterize...

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Published in:Journal of dermatology 2023-09, Vol.50 (9), p.1129-1139
Main Authors: Nwikue, Gospel, Olsson‐Brown, Anna, Aboheimed, Nourah, Yip, Vincent, Jolly, Carol, Luchian, Andreea, Ressel, Lorenzo, Sharma, Anurag, Bergfeld, Wilma, Ahmed, Shaheda, Dickinson, Anne, Pirmohamed, Munir, Carr, Daniel F.
Format: Article
Language:English
Subjects:
Apoptosis
Biomarkers - metabolism
Biopsy
Cytotoxicity
Dermatitis
Doxycycline
Enzyme-linked immunosorbent assay
Etanercept
Etanercept - pharmacology
Etanercept - therapeutic use
Explants
high‐mobility group box 1
HMGB1 Protein
Humans
Image processing
Immune checkpoint inhibitors
Keratinocytes - metabolism
Mobility
Necroptosis
Necrosis
Original
Skin
Stevens-Johnson Syndrome - diagnosis
Stevens–Johnson syndrome
Toxic epidermal necrolysis
Toxicity
Tumor necrosis factor
Tumor Necrosis Factor-alpha
Tumor necrosis factor-TNF
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Summary:Decreased epidermal high‐mobility group box 1 (HMGB1) expression is an early marker of epidermal injury in Stevens–Johnson syndrome/toxic epidermal necrolysis (SJS/TEN). Etanercept, an anti‐tumor necrosis factor therapeutic, is effective in the treatment of SJS/TEN. The objective was to characterize antitumor necrosis factor‐alpha (TNF‐α)‐mediated HMGB1 keratinocyte/epidermal release and etanercept modulation. HMGB1 release from TNF‐α treated (± etanercept), or doxycycline‐inducible RIPK3 or Bak‐expressing human keratinocyte cells (HaCaTs) was determined by western blot/ELISA. Healthy skin explants were treated with TNF‐α or serum (1:10 dilution) from immune checkpoint inhibitor‐tolerant, lichenoid dermatitis or SJS/TEN patients ± etanercept. Histological and immunohistochemical analysis of HMGB1 was undertaken. TNF‐α induced HMGB1 release in vitro via both necroptosis and apoptosis. Exposure of skin explants to TNF‐α or SJS/TEN serum resulted in significant epidermal toxicity/detachment with substantial HMGB1 release which was attenuated by etanercept. Whole‐slide image analysis of biopsies demonstrated significantly lower epidermal HMGB1 in pre‐blistered SJS/TEN versus control (P 
ISSN:0385-2407
1346-8138
DOI:10.1111/1346-8138.16847