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 ORCID: 0000-0003-1640-2816, Ogiji, Emeka D, Jolly, Carol ORCID: 0000-0002-4663-862X, Ressel, Lorenzo ORCID: 0000-0002-6614-1223, Sharma, Anurag, Bergfeld, Wilma, Liu, Xuan, Khirwadkar, Nitin, Bellon, Teresa et al (show 6 more authors) (2023) TNF-α-Mediated Keratinocyte Expression and Release of Matrix Metalloproteinase 9: Putative Mechanism of Pathogenesis in Stevens-Johnson Syndrome/Toxic Epidermal Necrolysis. JOURNAL OF INVESTIGATIVE DERMATOLOGY, 143 (6). 1023-+.

[img] Microsoft Word
MMP9_TNF_v1 Post_Author_Review.doc - Author Accepted Manuscript
Download (473kB)

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.

Item Type: Article
Uncontrolled Keywords: Keratinocytes, Humans, Stevens-Johnson Syndrome, Tumor Necrosis Factor-alpha, Matrix Metalloproteinase 9, Etanercept
Divisions: Faculty of Health and Life Sciences
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 Jan 2023 11:11
Last Modified: 18 Oct 2023 11:59
DOI: 10.1016/j.jid.2022.11.024
Related URLs:
URI: https://livrepository.liverpool.ac.uk/id/eprint/3166848
Dimensions
Altmetric
CORE (COnnecting REpositories)