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Cytotoxicity of crystals involves RIPK3-MLKL-mediated necroptosis

Author

Listed:
  • 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
    Walter Brendel Center for Experimental Medicine, University of Munich)

  • Christoph Reichel

    (Head and Neck Surgery, University of Munich
    Walter Brendel Center for Experimental Medicine, 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
    Nephropath)

  • Stefan Krautwald

    (Christian-Albrechts-University)

  • Andreas Linkermann

    (Christian-Albrechts-University)

  • Hans-Joachim Anders

    (Medizinische Klinik und Poliklinik IV, Klinikum der Universität)

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.

Suggested Citation

  • 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 Zuc, 2016. "Cytotoxicity of crystals involves RIPK3-MLKL-mediated necroptosis," Nature Communications, Nature, vol. 7(1), pages 1-15, April.
    • Handle: RePEc:nat:natcom:v:7:y:2016:i:1:d:10.1038_ncomms10274
    DOI: 10.1038/ncomms10274
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