Apoptosis represents a conserved mechanism of programmed cell death
[1][106]. Neutrophils die by constitutive apoptosis, an essential mechanism for neutrophil functional shutdown regulation
[2][1][53,106]. Apoptotic neutrophils are characterised by a series of typical morphological features such as cytoplasmic shrinkage, nuclear condensation, DNA fragmentation and membrane blebbing
[3][113]. They must display engulfment signals, known as “find-me” and “eat me” signals on their plasma membranes, such as the expression of today most studied phosphatidylserine receptor or calreticulin
[4][5][3][70,72,113], which permit recognition and phagocytic engulfment of dying cells by macrophages (efferocytosis)
[4][70]. Apoptosis depends on the balance between pro- (e.g., BAX, BAK) and anti-apoptotic (e.g., BCL-2, BCL-B, BCL-xL, BCL-W, MCL-1, A1) factors, which are both members of the B-cell lymphoma-2 (BCL-2) family of proteins
[6][114]. The anti-apoptotic protein myeloid cell leukemia sequence 1 (MCL-1) plays a key role in the regulation of neutrophil apoptosis
[3][7][8][113,115,116]. Important to note, cell cycle regulatory proteins, that in other cell types serve to control proliferation, in neutrophils, surprisingly, regulate apoptosis and survival
[1][9][106,117]. Thus, as neutrophil-specific regulatory factors, proliferating cell nuclear antigen (PCNA), myeloid nuclear differentiation antigen (MNDA) and cyclin-dependent kinases (CDKs) are identified
[1][9][106,117]. These neutrophil-specific regulatory proteins are localized in the nucleus of proliferating cells, while in mature neutrophils they are located in the cytoplasm where they act as pro-survival (PCNA, CDKs) or pro-apoptotic (MNDA) factors
[1][9][106,117]. Neutrophil apoptosis is usually initiated by the intrinsic or extrinsic apoptotic pathway
[10][118]. The intrinsic pathway mediates constitutive neutrophil apoptosis, which is driven by the permeabilisation of the mitochondrial outer membrane and subsequent release of cytohrome c from mitochondria, which leads to the activation of caspase-9, which in turn causes the activation of frequently activated death protease, caspase-3
[4][11][70,119]. The extrinsic pathway of neutrophil apoptosis is induced by ligation of TNF receptor superfamily cell surface death receptors, which drives caspase-8 dependent activation of caspase-3
[4][3][70,113].
Neutrophil apoptosis represents a pro-resolution mechanism that limits the extent of inflammation and consequently tissue injury, since efferocytosis occurs before the plasma membrane of apoptotic cells becomes leaky
[3][113]. Therefore, whereas nonlytic apoptotic cell death allows controlled removal of cells and promote healing and anti-inflammatory responses, pathways ending with loss of cell membrane integrity, such as NETotic death, necrosis and necroptosis, results in leakage of pro-inflammatory and toxic cell contents into the extracellular space and may elicit deleterious proinflammatory responses
[12][13][110,111] (
Figure 1B). More importantly, dysregulated apoptotic neutrophil death, either upregulated or downregulated, is often linked solely to chronic inflammatory diseases like cancer
[13][111] or autoimmune diseases
[6][14][114,120]. Reduced neutrophil apoptosis supports inflammation, stroma remodeling, tumor angiogenesis and metastasis
[13][14][111,120].