Programmed Necrosis and Disease:We interrupt your regular programming to bring you necroinflammation

Abstract

Compared to the tidy and immunologically silent death during apoptosis, necrosis seems like a chaotic and unorganized demise. However, we now recognize that there is a method to its madness, as many forms of necrotic cell death are indeed programmed and function beyond lytic cell death to support homeostasis and immunity. Inherently more immunogenic than their apoptotic counterpart, programmed necrosis, such as necroptosis, pyroptosis, ferroptosis, and NETosis, releases inflammatory cytokines and danger-associated molecular patterns (DAMPs), skewing the milieu to a pro-inflammatory state. Moreover, impaired clearance of dead cells often leads to inflammation. Importantly, these pathways have all been implicated in inflammatory and autoimmune diseases, therefore careful understanding of their molecular mechanisms can have long lasting effects on how we interpret their role in disease and how we translate these mechanisms into therapy.

Fig. 1

Molecular pathways of cell death and their roles in inflammation. Depending on death stimuli and context, live cells can undergo apoptosis or programmed necrosis. When caspase 3/7-dependent apoptotic cells are timely scavenged by efferocytosis, efferocytes like macrophages release anti-inflammatory cytokines and prevent unwanted inflammation. In the absence of effective clearance, apoptotic cells are proceeded to secondary necrosis and elicit some inflammatory responses. Upon damage signals such as infection or metabolic stress, cells trigger genetically programmed necrosis. Necroptosis and pyroptosis are RIPK3-MLKL- and inflammasome-GSDMD-mediated processes, respectively, displaying typical lytic morphology similar to primary necrosis. In contrast, ferroptosis is triggered by lipid peroxidation, and shows damaged mitochondria and reduced cellular volume. NETosis is a ROS-induced lytic cell death resulting in the extrusion of neutrophil extracellular traps (NETs), consisting of genomic DNA complexed with cellular proteins. Programmed necrotic cells generally release DAMPs and inflammatory cytokines that stimulate innate immune cells and promote necroinflammation

Fig. 2

Systemic spread of necroinflammation. Programmed necrosis or defective efferocytosis of dying cells can initiate local inflammation. DAMPs and proinflammatory cytokines derived from necrotic cells and subsequently activated immune cells provide feed-forward signals reinforcing programmed necrosis in more cells. Continuing the vicious death cycle allows the damage of barrier function, the spread of necroinflammation to systemic level, which may ultimately cause devastating multi-organ failure