Apoptosis represents a conserved mechanism of programmed cell death
[106][1]. Neutrophils die by constitutive apoptosis, an essential mechanism for neutrophil functional shutdown regulation
[53,106][2][1]. Apoptotic neutrophils are characterised by a series of typical morphological features such as cytoplasmic shrinkage, nuclear condensation, DNA fragmentation and membrane blebbing
[113][3]. 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
[70[4][5][3],
72,113], which permit recognition and phagocytic engulfment of dying cells by macrophages (efferocytosis)
[70][4]. 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
[114][6]. The anti-apoptotic protein myeloid cell leukemia sequence 1 (MCL-1) plays a key role in the regulation of neutrophil apoptosis
[113,115,116][3][7][8]. Important to note, cell cycle regulatory proteins, that in other cell types serve to control proliferation, in neutrophils, surprisingly, regulate apoptosis and survival
[106,117][1][9]. Thus, as neutrophil-specific regulatory factors, proliferating cell nuclear antigen (PCNA), myeloid nuclear differentiation antigen (MNDA) and cyclin-dependent kinases (CDKs) are identified
[106,117][1][9]. 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
[106,117][1][9]. Neutrophil apoptosis is usually initiated by the intrinsic or extrinsic apoptotic pathway
[118][10]. 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
[70,119][4][11]. 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
[70,113][4][3].
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
[113][3]. 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
[110,111][12][13] (
Figure 1B). More importantly, dysregulated apoptotic neutrophil death, either upregulated or downregulated, is often linked solely to chronic inflammatory diseases like cancer
[111][13] or autoimmune diseases
[114,120][6][14]. Reduced neutrophil apoptosis supports inflammation, stroma remodeling, tumor angiogenesis and metastasis
[111,120][13][14].