Cytotoxicity of crystals involves RIPK3-MLKL-mediated necroptosis
#MMPMID26817517
Mulay SR
; Desai J
; Kumar SV
; Eberhard JN
; Thomasova D
; Romoli S
; Grigorescu M
; Kulkarni OP
; Popper B
; Vielhauer V
; Zuchtriegel G
; Reichel C
; Bräsen JH
; Romagnani P
; Bilyy R
; Munoz LE
; Herrmann M
; Liapis H
; Krautwald S
; Linkermann A
; Anders HJ
Nat Commun
2016[Jan]; 7
(?): 10274
PMID26817517
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Crystals cause injury in numerous disorders, and induce inflammation via the
NLRP3 inflammasome, however, it remains unclear how crystals induce cell death.
Here we report that crystals of calcium oxalate, monosodium urate, calcium
pyrophosphate dihydrate and cystine trigger caspase-independent cell death in
five different cell types, which is blocked by necrostatin-1. RNA interference
for receptor-interacting protein kinase 3 (RIPK3) or mixed lineage kinase domain
like (MLKL), two core proteins of the necroptosis pathway, blocks crystal
cytotoxicity. Consistent with this, deficiency of RIPK3 or MLKL prevents oxalate
crystal-induced acute kidney injury. The related tissue inflammation drives
TNF-?-related necroptosis. Also in human oxalate crystal-related acute kidney
injury, dying tubular cells stain positive for phosphorylated MLKL. Furthermore,
necrostatin-1 and necrosulfonamide, an inhibitor for human MLKL suppress
crystal-induced cell death in human renal progenitor cells. Together,
TNF-?/TNFR1, RIPK1, RIPK3 and MLKL are molecular targets to limit crystal-induced
cytotoxicity, tissue injury and organ failure.
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