Figure 10: Schematic illustration of crystal-induced necroptosis and inflammation (necroinflammation).

During crystallophathies, crystals are formed and deposited inside the organ, for example, kidney stone disease or joint, for example, gouty arthritis. Upon crystallization, crystals are phagocytized by parenchymal cells where they activate the RIPK1, RIPK3 and MLKL pathway of necroptosis, a prototype form of regulated necrosis, by inducing a series of phosphorylation events. Cellular necroptosis lead to release of DAMPs, which activate immune cells surrounding the parenchymal cells. Activated immune cells release pro-inflammatory cytokines, for example, IL-1β, IL-6 and TNF-α and so on. Pro-inflammatory cytokines like TNF-α can also activate the RIPK1, RIPK3 and MLKL pathway of necroptosis via TNFR1. The auto-amplification loop between cell death and inflammation, called necroinflammation, leads to aggravation of tissue injury, and if remain uncontrolled then to organ failure. In the current settings, the loop of crystal-induced necroinflammation can be blocked by using a soluble TNFR1-hIgG1 fusion protein etanercept to inhibit TNF-α, TNFR inhibitor R-7050, RIPK1 inhibitor necrostatin-1 or MLKL inhibitor necrosulfonamide. RIPK, receptor-interacting protein kinase; MLKL, mixed lineage kinase domain like; DAMPs, danger associated molecular patterns; IL, interleukin; TNF, tumour-necrosis factor; TNFR, tumour-necrosis factor receptor.