Cytotoxicity of Crystals Involves RIPK3-MLKL-mediated Necroptosis

Overview

Journal Nat Commun

Specialty Biology

Date 2016 Jan 29

PMID 26817517

Citations 123

Authors

Shrikant R Mulay

Jyaysi Desai

Santhosh V Kumar

Jonathan N Eberhard

Dana Thomasova

Simone Romoli

Melissa Grigorescu

Onkar P Kulkarni

Bastian Popper

Volker Vielhauer

Gabriele Zuchtriegel

Christoph Reichel

Jan Hinrich Brasen

Paola Romagnani

Rostyslav Bilyy

Luis E Munoz

Martin Herrmann

Helen Liapis

Stefan Krautwald

Andreas Linkermann

Hans-Joachim Anders

Affiliations

Soon will be listed here.

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.

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