Upregulated RIP3 Expression Potentiates MLKL Phosphorylation-Mediated Programmed Necrosis in Toxic Epidermal Necrolysis

Sue Kyung Kim, Woo Jung Kim, Jung Ho Yoon, Jae Hoon Ji, Michael J. Morgan, Hyeseong Cho, You Chan Kim, You Sun Kim

Research output: Contribution to journalArticlepeer-review

51 Scopus citations

Abstract

Toxic epidermal necrolysis (TEN) is a severe adverse drug reaction involving extensive keratinocyte death in the epidermis. Histologically, the skin from TEN patients exhibits separation at the dermo-epidermal junction and accompanying necrosis of epidermal keratinocytes. Receptor-interacting protein kinase-3 (RIP3 or RIPK3) is an essential part of the cellular machinery that executes "programmed", or "regulated", necrosis and has a key role in spontaneous cell death and inflammation in keratinocytes under certain conditions. Here we show that RIP3 expression is highly upregulated in skin sections from TEN patients and may therefore contribute to the pathological damage in TEN through activation of programmed necrotic cell death. The expression level of mixed lineage kinase domain-like protein (MLKL), a key downstream component of RIP3, was not significantly different in skin lesions of TEN. However, elevated MLKL phosphorylation was observed in the skin from TEN patients, indicating the presence of RIP3-dependent programmed necrosis. Importantly, in an in vitro model of TEN, dabrafenib, an inhibitor of RIP3, prevented RIP3-mediated MLKL phosphorylation and decreased cell death. Results from this study suggest that the high expression of RIP3 in keratinocytes from TEN patients potentiates MLKL phosphorylation/activation and necrotic cell death. Thus, RIP3 represents a potential target for treatment of TEN.

Original languageEnglish (US)
Pages (from-to)2021-2030
Number of pages10
JournalJournal of Investigative Dermatology
Volume135
Issue number8
DOIs
StatePublished - Aug 21 2015
Externally publishedYes

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Dermatology
  • Cell Biology

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