Figure 6

Schematic representation of molecular mechanisms of crystalline particle-induced necroptosis. After exposure, crystals or crystalline particles are phagocytized by human cells. The frustrated crystal phagocytosis leads to lysosomal destabilization and subsequent leakage of cathepsin B (or other lytic proteases) into the cytosol. This cytosolic cathepsin B binds directly to RIPK1, an indigenous inhibitor of necroptosis, and induces its degradation. The degradation of RIPK1 leads to the formation of the necrosome that consists of RIPK3 and MLKL. A series of auto/trans phosphorylation activate RIPK3 and MLKL, leading to formation of oligomers of MLKL, which then are translocated to different membranes, e.g. nucleus, endoplasmic reticulum, mitochondria and plasma membranes etc. After binding MLKL, oligomers induce pore formation in these membranes leading to necroptosis. Crystals or crystalline particle-induced necroptosis can be inhibited by blocking phagocytosis using cytochalasin D or necroptosis using RIPK1 inhibitors necrostatin-1s, RIPK3 inhibitor dabrafenib, and MLKL inhibitor necrosulfonamide. Cat-B: Cathepsin B, RIPK: Receptor interacting protein kinase, MLKL: Mixed lineage kinase domain-like.