FIGURE 1.

Schematic view of the interplay between different cell death modalities in the context of infection. During immune challenge, in infected macrophages (a) an autophagic process can be triggered by pathogen contact and the phagocyted microorganisms are targeted by an ubiquitin coat to autophagosomes and then to autolysosomes to be eliminated by acidic and enzymatic degradation. If microbes are persistent or escape from vacuolar compartments, under apoptosis blockade (e.g. by caspase 8 inactivation), alternative cell death programmes can be activated, releasing the pathogen to be neutralized by other immune cells, enhancing inflammation and activating the immune system. Thus, the cell can go undergo autophagic cell death, necroptosis induced by TLRs under caspase 8 inhibition, through the RIPK1‐RIPK3‐MLKL pathway or by microbial DNA through DAI‐RIPK3 interactions, or caspase 1‐dependent pyroptosis triggered by NOD receptors. On the other hand, in infected neutrophils (b) pathogen contact triggers an apoptotic process that ensures the safe disposal of the microbial components and toxins after its degradation and at the same time regulates neutrophil population during immune response. Alternatively, persistent pathogens can also activate NETosis, through the ERK‐NOX4 pathway, massive permeabilization and releasing of granule contents that cause neutrophil death, but the released extracellular traps enclose and destroy invader pathogens. Casp, caspase; DAI, DNA‐dependent activator of IFN‐regulatory factors; DAMPs, danger‐associated molecular patterns; ERK, extracellular signal‐regulated kinase; GSDMD, Gasdermin D; IL, interleukin; MLKL, mixed lineage kinase domain‐like protein; MPO, myeloperoxidase; NE, neutrophil elastase; NET, neutrophil extracellular trap; NOD, nucleotide‐binding and oligomerization domain; NOX, NAPH oxidase; PAD4, peptidylarginine deiminase 4; PAMPs, pathogen‐associated molecular patterns; RIPK, receptor‐interacting protein kinases; ROS, reactive oxygen species; TLRs, Toll‐like receptors