Upregulated RIP3 Expression Potentiates MLKL Phosphorylation-Mediated Programmed Necrosis in Toxic Epidermal Necrolysis.
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.
Department of Dermatology, Ajou University School of Medicine, Suwon, Korea; These authors contributed equally to this work.
Sue Kyung
SK
Kim
Department of Biochemistry, Ajou University School of Medicine, Suwon, Korea; Department of Biomedical Sciences, Graduate School, Ajou University, Suwon, Korea; These authors contributed equally to this work.
Woo-Jung
WJ
Kim
Department of Biochemistry, Ajou University School of Medicine, Suwon, Korea; Department of Biomedical Sciences, Graduate School, Ajou University, Suwon, Korea.
Jung-Ho
JH
Yoon
Genomic Instability Research Center, Ajou University School of Medicine, Suwon, Korea.
Jae-Hoon
JH
Ji
Department of Pharmacology, University of Colorado School of Medicine, Aurora, Colorado, USA.
Michael J
MJ
Morgan
Department of Biochemistry, Ajou University School of Medicine, Suwon, Korea; Department of Biomedical Sciences, Graduate School, Ajou University, Suwon, Korea.
Hyeseong
H
Cho
Department of Dermatology, Ajou University School of Medicine, Suwon, Korea.
You Chan
YC
Kim
Department of Biochemistry, Ajou University School of Medicine, Suwon, Korea; Department of Biomedical Sciences, Graduate School, Ajou University, Suwon, Korea. Electronic address: yousunkim@ajou.ac.kr.
You-Sun
YS
Kim
D000328:Adult; D000369:Aged, 80 and over; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology; D001706:Biopsy; D002478:Cells, Cultured; D002648:Child; D002675:Child, Preschool; D004817:Epidermis / Q000378:metabolism* / Q000473:pathology*; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology; D066298:In Vitro Techniques; D007365:Intercellular Junctions / Q000502:physiology; D015603:Keratinocytes / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D008875:Middle Aged; D009336:Necrosis / Q000378:metabolism / Q000473:pathology; D010091:Oximes / Q000494:pharmacology; D010766:Phosphorylation / Q000187:drug effects; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D011494:Protein Kinases / Q000378:metabolism*; D053422:Receptor-Interacting Protein Serine-Threonine Kinases / Q000378:metabolism*; D012867:Skin / Q000378:metabolism / Q000473:pathology; D013262:Stevens-Johnson Syndrome / Q000378:metabolism* / Q000473:pathology*; D015854:Up-Regulation / Q000502:physiology*
D007093:Imidazoles; D010091:Oximes; D047428:Protein Kinase Inhibitors; C570693:MLKL protein, human; D011494:Protein Kinases; C119705:RIPK3 protein, human; D053422:Receptor-Interacting Protein Serine-Threonine Kinases; C561627:dabrafenib