Cell death as part of innate immunity: Cause or consequence?

Abstract

Regulated or programmed cell death plays a critical role in the development and tissue organization and function. In addition, it is intrinsically connected with immunity and host defence. An increasing cellular and molecular findings cause a change in the concept of cell death, revealing an expanding network of regulated cell death modalities and their biochemical programmes. Likewise, recent evidences demonstrate the interconnection between cell death pathways and how they are involved in different immune mechanisms. This work provides an overview of the main cell death programmes and their implication in innate immunity not only as an immunogenic/inflammatory process, but also as an active defence strategy during immune response and at the same time as a regulatory mechanism.

Keywords: apoptosis; innate immunity; molecular pathways; necrosis; programmed cell death; regulated.

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

FIGURE 2

Overview of the main bacterial and viral mechanisms to suppress PCD such as apoptosis and major forms of programmed necrosis. Both extracellular and intracellular bacteria have developed pore‐forming secretion systems to deliver specific proteins inside the cell to inhibit the main targets of multiple processes including cell death. Bacterial suppression of PCD is based on proteases and inhibitory proteins that decrease the integrity/activity of host cell factors. Some bacteria can also produce nucleases and DNA binding proteins that impair NET formation. On the other hand, viruses (including DNA and RNA viruses) deliver their genetic material into the cell where it is processed by the host cell machinery to undergo transcription and translation or direct translation, leading to the expression of viral proteins. These virulence factors suppress PCD mainly interacting with target proteins to sequester them or occluding binding domains to impair protein–protein interaction. Black arrows represent sequential steps in a process/pathway, and red arrows represent the final steps in a given pathway. Red crosses represent inhibition or blockade of a protein/pathway. ASC, apoptosis‐associated speck‐like protein; BH3‐p, BH3 only domain‐containing proteins; C, cytochrome c; Casp, caspase; FADD, Fas‐associated protein with death domain; GSDMD, Gasdermin D; IL, interleukin; MLKL, mixed lineage kinase domain‐like protein; NET, neutrophil extracellular trap; NLRP3, Nod‐like receptor pyrin‐containing protein 3; Pn, pyrin domain; RIPK, receptor‐interacting protein kinases; TLRs, Toll‐like receptors; TRIF, TIR domain‐containing adapter‐inducing interferon‐β