Repairing plasma membrane damage in regulated necrotic cell death

The plasma membrane performs a central role in maintaining cellular homeostasis and viability by acting as a semi-permeable barrier separating the cell from its surroundings. Under physiological conditions, it is constantly exposed to different kinds of stress, such as from pore-forming proteins/toxins and mechanical activity, that compromises its integrity resulting in cells developing various ways to cope with these dangers to survive. These plasma membrane repair mechanisms are initiated by the rapid influx of extracellular Ca²⁺ ions and are thus hinged on the activity of various Ca²⁺-binding proteins. The cell's response to membrane damage also depends on the nature and extent of the stimuli as well as the cell type, and the mechanisms involved are believed to be not mutually exclusive. In regulated necrotic cell death, specifically necroptosis, pyroptosis, and ferroptosis, plasma membrane damage ultimately causes cell lysis and the release of immunomodulating damage-associated molecular patterns. Here, I will discuss how these three cell death pathways are counterbalanced by the action of ESCRT (Endosomal Sorting Complex Required for Transport)-III-dependent plasma membrane repair mechanism, that eventually affects the profile of released cytokines and cell-to-cell communication. These highlight a crucial role that plasma membrane repair play in regulated necrosis, and its potential as a viable target to modulate the immune responses associated with these pathways in the context of the various human pathologies where these cell death modalities are implicated.