Figure 3 Molecular mechanisms of crystal-induced necroinflammation Figure 3 | Molecular mechanisms of crystal-induced necroinflammation. Supersaturation of solutes in the urine leads to deposition of crystals in the tubular lumen, which activate signalling pathways that lead to tubular cell death (through necroptosis). Phagocytosis of crystals causes lysosomal destabilization and release of cathepsin B (cat-B), which cleaves receptor-interacting serine/threonine-protein kinase (RIPK) 1, a negative regulator of necroptosis. In conditions where caspase-8 is inhibited, RIPK1 degradation triggers the formation of the RIPK3–MLKL necrosome complex, resulting in tubular cell necroptosis. Dying tubular cells release numerous damage-associated molecular patterns (DAMPs) and alarmins, which initiate inflammation. Dendritic cells and macrophages phagocytose crystals present in the interstitial compartment. Subsequent lysosomal destabilization releases cat-B and reactive oxygen species (ROS), which activate the NLRP3 inflammasome and induce secretion of mature IL-1β by dendritic cells, triggering IL-1 receptor (IL-1R)-dependent inflammation in the kidney. The TNF receptor (TNFR) pathway can activate NF-κB, which contributes to the activation of the inflammasome. RIPK3 and MLKL can also activate the NLRP3 inflammasome but whether this process is triggered by crystals is still unknown. Certain proinflammatory cytokines such as TNF can trigger regulated necrosis in renal cells through the TNFR, leading to further DAMP release. This process leads to an auto-amplification loop of crystal-induced necroinflammation. DAMPs such as histones act as a central mediator of the necroinflammation loop as they induce both Toll-like receptor-dependent inflammation and charge-dependent cell necrosis. Mulay, S. R. & Anders, H.-J. (2017) Crystal nephropathies: mechanisms of crystal-induced kidney injury Nat. Rev. Nephrol. doi:10.1038/nrneph.2017.10