Knowledge of the mechanisms underlying programmed necrosis is yet too incomplete and does not allow for a universal (in terms of considering a panoply of different cell types) definition. The definition thus remains descriptive (based principally on the morphological features) and negative (based on the elimination of other cell death mechanisms). There are currently only two discriminatory criteria coming from the genetic (for the first) and biochemical (for the second) studies. First criterion concerns the apparent dependency of the programmed necrosis on cyclophilin D (cypD): genetic ablation of this component of the mitochondrial permeability transition (PT) pore confers resistance to (programmed) necrosis without preventing other forms of cell death (Baines et al. 2005; Basso et al. 2005; Nakagawa et al. 2005; Schinzel et al. 2005). The second criterion comes from the biochemical studies and deals with the structural alterations of the plasma membrane at the early stages of programmed necrosis. Cells undergoing programmed necrosis display Annexin V-detectable phosphatidylserine (PS) exposure, but in contrast to what is seen in apoptosis, Annexin V-labelling never appears before plasma membrane permeabilization (assessed by PI labelling and LDH release). The programmed necrosis-related Annexin V-labelling does not appear as an artefact since the cells dying by programmed necrosis can be efficiently phagocyted (Boujrad et al. 2007). Altogether, this strongly suggests that PS exposed to the extra-cellular space serves as a functional "eat me" signal. The capacity of monocytes/macrophages to eliminate MNNG-treated cells before they undergo lysis due to plasma membrane permeabilization (Boujrad et al. 2007), argues in favour of a very short delay between PS exposure and plasma membrane permeabilization. Although such delay is probably undetectable by current methods (meaning that both Annexin V-labelling and LDH leakiness are detected concomitantly), it might be a specific biochemical hallmark of programmed necrosis. Consistent with this is the fact that the delay between Annexin V-exposure and LDH release is much longer in apoptosis, allowing for a detection of Annexin V-positive/PI-negative cells before detection of double-positive cells. However, it should be kept in mind that, alternatively, cells dying by programmed necrosis might display specific (i.e. different from those used to clear apoptotic cells) and yet unknown "eat me" signals that can be used by macrophages to clear necrotic cells (Krysko et al. 2006).
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