Crystals induce cell death in the kidney through necroptosis

Crystals are deposits of various sizes and shapes composed of atoms, ions or biomolecules, frequently with tissue injury, inflammation and remodelling. Two mechanisms may explain this association: (I) nucleation or crystal growth from a seed crystal formed on a surface medium, for example tubular epithelial cells, urolithiasis forming at Randall’s plaques, calcifications in injured tendons, damaged cartilage or atheromatous vascular lesions, (II) crystal formation itself causes tissue injury and inflammation, for example in gouty arthritis, pulmonary silicosis or asbestosis, cholesterol crystals driving atherogenesis and in oxalate, cystine or urate nephropathy.

Crystals trigger tissue inflammation via the NLRP3 inflammasome- and caspase-1-mediated secretion of IL-1b and IL-18. However, crystals also exert direct cytotoxic effects leading to necrotic rather than apoptotic cell death. It is still unknown, whether crystal deposition causes necrosis in a passive mechanical or in one of the recently identified modalities of regulated cell death.

Researchers 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.

http://www.nature.com/ncomms/2016/160128/ncomms10274/full/ncomms10274.html

Edited January 28th 2016