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

Anna Olsson-Brown, Vincent Yip, Emeka D Ogiji, Carol Jolly, Lorenzo Ressel, Anurag Sharma, Wilma Bergfeld, Xuan Liu, Nitin Khirwadkar, Teresa Bellon, Anne Dickinson, Shaheda Ahmed, Abigail Langton, Rachel Watson, Munir Pirmohamed, Daniel F Carr

Research output: Contribution to journalArticlepeer-review

Abstract

Stevens‒Johnson syndrome and toxic epidermal necrolysis (SJS/TEN) are severe cutaneous adverse drug reactions characterized by widespread keratinocyte cell death and epidermal detachment. At present, there is little understanding of how the detachment occurs or how it is abrogated by the TNF-α inhibitor etanercept, an effective SJS/TEN treatment. RNA sequencing was used to identify upregulated transcripts in formalin-fixed paraffin-embedded SJS/TEN skin biopsies. Epidermal matrix metalloproteinase 9 (MMP9) expression was assessed by immunohistochemistry in skin biopsies and cultured human skin explants exposed to serum from patients with cutaneous adverse drug reactions. TNF-α‒induced MMP9 expression and activity and its abrogation by etanercept were determined using the HaCaT immortalized keratinocyte cell line. Epidermal MMP9 expression was significantly higher in SJS/TEN skin (70.6%) than in healthy control skin (0%) (P = 0.0098) and nonbullous skin reactions (10.7%) (P = 0.0002). SJS/TEN serum induced significant MMP9 expression and collagenase activity in healthy skin explants, which was reduced by etanercept. Etanercept was also able to negate the TNF-α‒induced MMP9 expression in the HaCaT cell line. Data suggest that elevated epidermal MMP9 expression and collagenase activity are a putative pathogenic mechanism in SJS/TEN, which is limited by etanercept. Modulation of MMP9 expression and activity represents, to our knowledge, a previously unreported therapeutic target for the treatment of SJS/TEN.

Original languageEnglish
Pages (from-to)1023-1030.e7
JournalThe Journal of investigative dermatology
Volume143
Issue number6
Early online date26 Dec 2022
DOIs
Publication statusPublished - 1 Jun 2023

Keywords

  • Humans
  • Stevens-Johnson Syndrome/etiology
  • Tumor Necrosis Factor-alpha/therapeutic use
  • Matrix Metalloproteinase 9
  • Etanercept/pharmacology
  • Keratinocytes/pathology

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