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Nat Commun. 2016 Jan 28;7:10274. doi: 10.1038/ncomms10274.

Cytotoxicity of crystals involves RIPK3-MLKL-mediated necroptosis.

Author information

1
Medizinische Klinik und Poliklinik IV, Klinikum der Universität, München, Munich 80336, Germany.
2
Department of Anatomy and Cell Biology, Ludwig-Maximilians Universität, Munich 80336, Germany.
3
Department of Otorhinolaryngology, Head and Neck Surgery, University of Munich, Munich 81377, Germany.
4
Walter Brendel Center for Experimental Medicine, University of Munich, Munich 81377, Germany.
5
Department of Nephropathology, Institute for Pathology, Hannover Medical School, Hannover 30625, Germany.
6
Excellence Centre for Research, Transfer and High Education for the Development of De Novo Therapies (DENOTHE), University of Florence, Florence 50139, Italy.
7
Danylo Halytsky Lviv National Medical University, Lviv 79010, Ukraine.
8
Department for Internal Medicine, University Hospital Erlangen, Institute for Clinical Immunology, Erlangen 91054, Germany.
9
Department of Pathology and Immunology, Washington University School of Medicine, Saint Louis, Missouri 63110, USA.
10
Nephropath, Little Rock, Arkansas 72211, USA.
11
Division of Nephrology and Hypertension, Christian-Albrechts-University, Kiel 24105, Germany.

Abstract

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-α-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-α/TNFR1, RIPK1, RIPK3 and MLKL are molecular targets to limit crystal-induced cytotoxicity, tissue injury and organ failure.

PMID:
26817517
PMCID:
PMC4738349
DOI:
10.1038/ncomms10274
[Indexed for MEDLINE]
Free PMC Article

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