Fueling the Flames: Mammalian Programmed Necrosis in Inflammatory Diseases

Programmed necrosis or necroptosis is an inflammatory form of cell death driven by TNF-like death cytokines, toll-like receptors, and antigen receptors. Unlike necrosis induced by physical trauma, a dedicated pathway is involved in programmed necrosis. In particular, a kinase complex composed of the receptor interacting protein kinase 1 (RIPK1) and RIPK3 is a central step in necrotic cell death. Assembly and activation of this RIPK1–RIPK3 “necrosome” is critically controlled by protein ubiquitination, phosphorylation, and caspase-mediated cleavage events. The molecular signals cumulate in formation of intracellular vacuoles, organelle swelling, internal membrane leakage, and eventually plasma membrane rupture. These morphological changes can result in spillage of intracellular adjuvants to promote inflammation and further exacerbate tissue injury. Because of the inflammatory nature of necrosis, it is an attractive pathway for therapeutic intervention in acute inflammatory diseases.Necrosis and tissue inflammation are two tightly linked phenomena. Cell injury induced by excessive trauma such as heat shock and osmotic shock can result in cell death with “necrotic morphology.” These relatively nonspecific means to trigger necrosis have contributed to the notion that necrosis is caused by excessive insults and does not involve elaborate intracellular signaling pathways. In contrast to the notion that necrosis is associated with harmful pathologies, recent work indicates that necrosis can have beneficial roles in certain biological responses. Proteomic approaches and RNA interference screens have identified several crucial regulators of necrosis induced by TNF-like death cytokines. Because a dedicated molecular circuitry is involved, the terms “programmed necrosis” and “necroptosis” have been used to distinguish these types of necrotic cell death from necrosis induced by physical trauma or insults. Here I will discuss the molecular pathway that regulates programmed necrosis/necroptosis. For the sake of simplicity, we will use the term necrosis to refer to programmed necrosis induced by defined death cytokines.