FIGURE 2: The three waves of immunomodulatory processes during necroptosis. Schematic summary and modelling of our results showing the three immunomodulatory waves during necroptosis. (A) Initiation of necroptotic signal transduction results in MLKL phosphorylation, triggering the first immunomodulatory signal (B) as phosphatidylserine (PS) is exposed on the outer membrane and ‘necroptotic bodies’ are released. (C) A second wave occurs when outer membrane integrity is compromised due to MLKL pore formation resulting in cytoplasmic DAMPs release. (D) The last wave of necroptotic immunomodulatory signal occurs when nuclear and organelle membrane integrity are lost leading to release of their DAMPs. (E) Phagocytosis of cells externalizing PS or ‘necroptotic bodies’ containing immunomodulatory intracellular factors. (F) MLKL inhibition can result in rescue of necroptotic cells in the early stages of necroptosis.