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



Nwikue, Gospel, Olsson-Brown, Anna, Aboheimed, Nourah, Yip, Vincent ORCID: 0000-0003-1640-2816, Jolly, Carol ORCID: 0000-0002-4663-862X, Luchian, Andreea, Ressel, Lorenzo ORCID: 0000-0002-6614-1223, Sharma, Anurag, Bergfeld, Wilma, Ahmed, Shaheda
et al (show 3 more authors) (2023) 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. JOURNAL OF DERMATOLOGY, 50 (9). pp. 1129-1139.

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Abstract

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 < 0.05). Keratinocyte HMGB1 release, predominantly caused by necroptosis, can be attenuated by etanercept. Although TNF-α is a key mediator of epidermal HMGB1 release, other cytokines/cytotoxic proteins also contribute. Skin explant models represent a potential model of SJS/TEN that could be utilized for further mechanistic studies and targeted therapy screening.

Item Type: Article
Uncontrolled Keywords: high-mobility group box 1, Stevens-Johnson syndrome, toxic epidermal necrolysis, tumor necrosis factor alpha
Divisions: Faculty of Health and Life Sciences
Faculty of Health and Life Sciences > Institute of Life Courses and Medical Sciences
Faculty of Health and Life Sciences > Institute of Life Courses and Medical Sciences > School of Medicine
Faculty of Health and Life Sciences > Institute of Infection, Veterinary and Ecological Sciences
Faculty of Health and Life Sciences > Institute of Systems, Molecular and Integrative Biology
Depositing User: Symplectic Admin
Date Deposited: 06 Jun 2023 07:43
Last Modified: 19 Oct 2023 10:13
DOI: 10.1111/1346-8138.16847
Open Access URL: https://onlinelibrary.wiley.com/doi/epdf/10.1111/1...
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URI: https://livrepository.liverpool.ac.uk/id/eprint/3170830