TNF-α‒Mediated Keratinocyte Expression and Release of Matrix Metalloproteinase 9: Putative Mechanism of Pathogenesis in Stevens‒Johnson Syndrome/Toxic Epidermal Necrolysis

Olsson‐Brown, Anna; Yip, Vincent; Ogiji, Emeka D; Jolly, Carol E.; Ressel, Lorenzo; Sharma, Anurag; Bergfeld, Wilma F.; Li, Xuan; Khirwadkar, Nitin; Bellón, Teresa; Dickinson, Anne; Ahmed, Shaheda; Langton, Abigail K.; Watson, Rachel; Pirmohamed, Munir; Carr, Daniel F.

doi:10.1016/j.jid.2022.11.024

Cited by 15 publications

(9 citation statements)

References 37 publications

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“…TNFα concentrations of the three sera were determined by ELISA as healthy control 2.92 pg/mL (0.29 pg/mL final concentration), lichenoid dermatitis 9.17 pg/mL (0.92 pg/mL final concentration), and SJS/TEN 12.25 pg/ mL (1.22 pg/mL final concentration). As previously described, 10 exposure of explants to ICI-induced SJS/TEN patient serum induced grade III pathology with intra-epidermal damage and necrosis in both duplicates. The addition of etanercept reduced the pathology to grade II in both instances (Supporting Information Table S4).…”

Section: Hmgb1 Expression and Supernatant Release In Healthy Skin Exp...supporting

confidence: 58%

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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,

Olsson‐Brown,

Aboheimed

et al. 2023

The Journal of Dermatology

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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.

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Section: Hmgb1 Expression and Supernatant Release In Healthy Skin Exp...supporting

confidence: 58%

“…As previously described and published, 10 4‐mm biopsies were taken from healthy skin tissue (Tissue Solutions Ltd). Anakinra was utilized as a positive control as previous observations suggest that at 10 μg/mL it induces a toxicity and epidermal separation phenotype in explants akin to SJS/TEN.…”

Section: Methodsmentioning

confidence: 99%

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,

Olsson‐Brown,

Aboheimed

et al. 2023

The Journal of Dermatology

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“…Serum from SJS/TEN patients also induced MMP9 expression in healthy skin explants which were reduced by etanercept. Furthermore, etanercept reduced TNF-α induced MMP9 expression in cell lines providing additional support for the potential role of etanercept as an SJS/TEN therapeutic agent ( 101 ).…”

Section: Other Considerations For Clinical Diagnosis and Managementmentioning

confidence: 83%

Updates in SJS/TEN: collaboration, innovation, and community

Marks,

Botta,

Abe

et al. 2023

Front. Med.

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Stevens-Johnson Syndrome/Toxic Epidermal Necrolysis (SJS/TEN) is a predominantly drug-induced disease, with a mortality rate of 15–20%, that engages the expertise of multiple disciplines: dermatology, allergy, immunology, clinical pharmacology, burn surgery, ophthalmology, urogynecology, and psychiatry. SJS/TEN has an incidence of 1–5/million persons per year in the United States, with even higher rates globally. One of the challenges of SJS/TEN has been developing the research infrastructure and coordination to answer questions capable of transforming clinical care and leading to improved patient outcomes. SJS/TEN 2021, the third research meeting of its kind, was held as a virtual meeting on August 28–29, 2021. The meeting brought together 428 international scientists, in addition to a community of 140 SJS/TEN survivors and family members. The goal of the meeting was to brainstorm strategies to support the continued growth of an international SJS/TEN research network, bridging science and the community. The community workshop section of the meeting focused on eight primary themes: mental health, eye care, SJS/TEN in children, non-drug induced SJS/TEN, long-term health complications, new advances in mechanisms and basic science, managing long-term scarring, considerations for skin of color, and COVID-19 vaccines. The meeting featured several important updates and identified areas of unmet research and clinical need that will be highlighted in this white paper.

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“…Monocyte could not only enhance consistent CTLs’ cytotoxicity but also activate TNF-receptor 1 (TNF-R1) mediated apoptosis pathway by TNF-α secretion, resulted in further epidermal destruction ( Tohyama et al, 2012 ; Su et al, 2017 ; Kuijper et al, 2020 ). Besides, Olsson-Brown et al (2022) reported a mechanism of TNF-α-induced matrix metalloproteinase 9 (MMP9) expression of keratinocytes in SJS/TEN. Recently, monocytes might play an important role in keratinocyte necroptosis, another keratinocyte’s death mechanism ( Saito, 2014 ).…”

Section: Mechanism Of Scarmentioning

confidence: 99%

Current understanding of genetic associations with delayed hypersensitivity reactions induced by antibiotics and anti-osteoporotic drugs

Wung¹,

Wang²,

Lai³

et al. 2023

Front. Pharmacol.

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Drug-induced delayed hypersensitivity reactions (DHRs) is still a clinical and healthcare burden in every country. Increasing reports of DHRs have caught our attention to explore the genetic relationship, especially life-threatening severe cutaneous adverse drug reactions (SCARs), including acute generalized exanthematous pustulosis (AGEP), drug reactions with eosinophilia and systemic symptoms (DRESS), Stevens–Johnson syndrome (SJS), and toxic epidermal necrolysis (TEN). In recent years, many studies have investigated the immune mechanism and genetic markers of DHRs. Besides, several studies have stated the associations between antibiotics-as well as anti-osteoporotic drugs (AOD)-induced SCARs and specific human leukocyte antigens (HLA) alleles. Strong associations between drugs and HLA alleles such as co-trimoxazole-induced DRESS and HLA-B*13:01 (Odds ratio (OR) = 45), dapsone-DRESS and HLA-B*13:01 (OR = 122.1), vancomycin-DRESS and HLA-A*32:01 (OR = 403), clindamycin-DHRs and HLA-B*15:27 (OR = 55.6), and strontium ranelate (SR)-SJS/TEN and HLA-A*33:03 (OR = 25.97) are listed. We summarized the immune mechanism of SCARs, update the latest knowledge of pharmacogenomics of antibiotics- and AOD-induced SCARs, and indicate the potential clinical use of these genetic markers for SCARs prevention in this mini review article.

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TNF-α‒Mediated Keratinocyte Expression and Release of Matrix Metalloproteinase 9: Putative Mechanism of Pathogenesis in Stevens‒Johnson Syndrome/Toxic Epidermal Necrolysis

Cited by 15 publications

References 37 publications

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

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

Updates in SJS/TEN: collaboration, innovation, and community

Current understanding of genetic associations with delayed hypersensitivity reactions induced by antibiotics and anti-osteoporotic drugs

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