Cytotoxicity of crystals involves RIPK3-MLKL-mediated necroptosis

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 Bräsen, Paola Romagnani, Rostyslav Bilyy, Luis E. Munoz, Martin Herrmann, Helen Liapis, Stefan Krautwald, Andreas Linkermann and Hans-Joachim Anders ()
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Shrikant R. Mulay: Medizinische Klinik und Poliklinik IV, Klinikum der Universität
Jyaysi Desai: Medizinische Klinik und Poliklinik IV, Klinikum der Universität
Santhosh V. Kumar: Medizinische Klinik und Poliklinik IV, Klinikum der Universität
Jonathan N. Eberhard: Medizinische Klinik und Poliklinik IV, Klinikum der Universität
Dana Thomasova: Medizinische Klinik und Poliklinik IV, Klinikum der Universität
Simone Romoli: Medizinische Klinik und Poliklinik IV, Klinikum der Universität
Melissa Grigorescu: Medizinische Klinik und Poliklinik IV, Klinikum der Universität
Onkar P. Kulkarni: Medizinische Klinik und Poliklinik IV, Klinikum der Universität
Bastian Popper: Ludwig-Maximilians Universität
Volker Vielhauer: Medizinische Klinik und Poliklinik IV, Klinikum der Universität
Gabriele Zuchtriegel: Head and Neck Surgery, University of Munich
Christoph Reichel: Head and Neck Surgery, University of Munich
Jan Hinrich Bräsen: Institute for Pathology, Hannover Medical School
Paola Romagnani: Excellence Centre for Research, Transfer and High Education for the Development of De Novo Therapies (DENOTHE), University of Florence
Rostyslav Bilyy: Danylo Halytsky Lviv National Medical University
Luis E. Munoz: University Hospital Erlangen, Institute for Clinical Immunology
Martin Herrmann: University Hospital Erlangen, Institute for Clinical Immunology
Helen Liapis: Washington University School of Medicine
Stefan Krautwald: Christian-Albrechts-University
Andreas Linkermann: Christian-Albrechts-University
Hans-Joachim Anders: Medizinische Klinik und Poliklinik IV, Klinikum der Universität

Nature Communications, 2016, vol. 7, issue 1, 1-15

Abstract: 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.

Date: 2016
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DOI: 10.1038/ncomms10274

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