Cytotoxicity of crystals involves RIPK3-MLKL-mediated necroptosis

Mulay SR, Desai J, Kumar SV, Eberhard JN, Thomasova D, Romoli S, Grigorescu M, Kulkarni OP, Popper B, Vielhauer V, Zuchtriegel G, Reichel C, Braesen JH, Romagnani P, Bilyy R, Munoz LE, Herrmann M, Liapis H, Krautwald S, Linkermann A, Anders HJ (2016)

Publication Type: Journal article

Publication year: 2016

Journal

Nature Communications Nature Publishing Group: Nature Communications

Book Volume: 7

Pages Range: 10274

DOI: 10.1038/ncomms10274

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-?-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.

Authors with CRIS profile

Luis Munoz Becerra Department of Medicine 3 – Rheumatology and Immunology Martin Herrmann Department of Medicine 3 – Rheumatology and Immunology

Involved external institutions

Klinikum der Universität München (Großhadern und Innenstadt) DE Germany (DE) Christian-Albrechts-Universität zu Kiel DE Germany (DE) Washington University US United States (USA) (US) Danylo Halytsky Lviv National Medical University / Львiвський Національний Медичний Унiверситет iм. Данила Галицького UA Ukraine (UA) Medizinische Hochschule Hannover (MHH) / Hannover Medical School DE Germany (DE) Ludwig-Maximilians-Universität (LMU) DE Germany (DE) Università degli Studi di Firenze / University of Florence IT Italy (IT)

How to cite

APA:

Mulay, S.R., Desai, J., Kumar, S.V., Eberhard, J.N., Thomasova, D., Romoli, S.,... Anders, H.-J. (2016). Cytotoxicity of crystals involves RIPK3-MLKL-mediated necroptosis. Nature Communications, 7, 10274. https://doi.org/10.1038/ncomms10274

MLA:

Mulay, Shrikant R., et al. "Cytotoxicity of crystals involves RIPK3-MLKL-mediated necroptosis." Nature Communications 7 (2016): 10274.

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