Pyroptosis

Pyroptosis is a highly inflammatory form of programmed cell death that occurs most frequently upon infection with intracellular pathogens and is likely to form part of the antimicrobial response. In this process, immune cells recognize foreign danger signals within themselves, release pro-inflammatory cytokines, swell, burst and die. The released cytokines attract other immune cells to fight the infection and contribute to inflammation in the tissue. Pyroptosis promotes the rapid clearance of various bacterial and viral infections by removing intracellular replication niches and enhancing the host's defensive responses. However, in pathogenic chronic diseases, the inflammatory response does not eradicate the primary stimulus, as would normally occur in most cases of infection or injury, and thus a chronic form of inflammation ensues that ultimately contributes to tissue damage. Some examples of pyroptosis include Salmonella-infected macrophages and abortively HIV-infected T helper cells. Pyroptosis is a highly inflammatory form of programmed cell death that occurs most frequently upon infection with intracellular pathogens and is likely to form part of the antimicrobial response. In this process, immune cells recognize foreign danger signals within themselves, release pro-inflammatory cytokines, swell, burst and die. The released cytokines attract other immune cells to fight the infection and contribute to inflammation in the tissue. Pyroptosis promotes the rapid clearance of various bacterial and viral infections by removing intracellular replication niches and enhancing the host's defensive responses. However, in pathogenic chronic diseases, the inflammatory response does not eradicate the primary stimulus, as would normally occur in most cases of infection or injury, and thus a chronic form of inflammation ensues that ultimately contributes to tissue damage. Some examples of pyroptosis include Salmonella-infected macrophages and abortively HIV-infected T helper cells. The initiation of pyroptosis in infected macrophages is caused by the recognition of flagellin components of Salmonella and Shigella species (and similar pathogen-associated molecular patterns (PAMPs) in other microbial pathogens) by NOD-like receptors (NLRs). These receptors function like plasma membrane toll-like receptors (TLRs), but recognize antigens located within the cell rather than outside of it. In contrast to apoptosis, pyroptosis requires the function of the enzyme caspase-1. Caspase-1 is activated during pyroptosis by a large supramolecular complex termed the pyroptosome (also known as an inflammasome). Only one large pyroptosome is formed in each macrophage, within minutes after infection. Biochemical and mass spectroscopic analysis revealed that this pyroptosome is largely composed of dimers of the adaptor protein ASC (apoptosis-associated speck protein containing a CARD or Caspase activation and recruitment domain). Unlike apoptosis, cell death by pyroptosis results in plasma-membrane rupture and the release of damage-associated molecular pattern (DAMP) molecules such as ATP, DNA and ASC oligomers (specks) into the extracellular milieu, including cytokines that recruit more immune cells and further perpetuate the inflammatory cascade in the tissue. These processes are in marked contrast to the packaging of cellular contents and non-inflammatory phagocytic uptake of membrane-bound apoptotic bodies that characterizes apoptosis. This type of inherently proinflammatory programmed cell death was named 'pyroptosis' in 2001 by Dr. Brad T. Cookson, an associate professor of microbiology and laboratory medicine of University of Washington. The Greek 'pyro' refers to fire and 'ptosis' means falling. The apparent meaning of the combined word 'pyroptosis' is therefore 'the falling of fire', which here refers to the process of pro-inflammatory chemical signals bursting out of a host cell. Pyroptosis has a distinct morphology and mechanism compared to other forms of cell death. However, this form of cell death is akin to necrosis. It was suggested that microbial infection was the main evolutionary pressure for this pathway. Infection can launch a 'self-destruct' and warning system in the host cell. Two types of receptors that belong to different families of pattern recognition receptors (PRRs) are present in the pyroptosis to sense intracellular and extracellular 'danger' signals. These are Nod-like receptors (NLRs) and Toll-like receptors (TLRs). The 'danger' signals can be given off by invasive pathogens, or by an injury to a tissue, which can all be recognised by the host cells' receptors. That recognition will determine the fate of the host cell by a distinct mechanism, i.e. it will induce either the production of inflammatory chemical messengers termed 'cytokines' or programmed cell death. Commonly found cytokines are tumour necrosis factor (TNF), IL-6, IL-8, type I interferons (IFNs) and Interferon regulatory factor (IRFs). The inflammatory response is cell-death independent. In terms of cell death, although the activation route of caspase-1 is varied, the downstream signalling pathway will converge to result in the pyroptotic cell death. Cell lysis occurs upon the formation of pores, of an estimated diameter of 1.1-2.4 nm, in the cell membrane, which disrupts the cellular ionic gradient. The resulting increase in osmotic pressure causes an influx of water followed by cell swelling and bursting. At the same time, the cytosolic contents release via the channels of the pores. The process is much like punctures in a water balloon. Subsequently, the inactive pro-inflammatory cytokines are further cleaved by caspase-1 and become activated. Moreover, DNA cleavage with retained integrity and nuclear condensation has also been found to be associated with the process. Toll like receptors (TLRs) recognize Pathogen-Associated Molecular Patterns (PAMPs) that are located either in cell surface or within endosomes. The resulting recognition will initiate the signalling pathway, including the activation of transcription factors NF-κB and MAPKs. This in turn will be responsible for the production of inflammatory cytokines such as IFN α/β, TNF and IL-12. In addition, pro-IL-1β and pro-IL-18 will be released to be processed by cysteine-mediated caspase-1. NOD-like receptors (NLRs) consist of more than 20 subsets, including NOD1 and NOD2, NLRP3 (also known as NALP3), NLRC4. All recognize bacterial, viral and toxic foreign products that are introduced into the host cell cytosol. Upon recognition, NOD1 and NOD2 function similarly to the TLRs, producing and processing inflammatory cytokines. Some of these subsets such as NLRP3 could also activate caspase-1 dependent cell death, accompanied by pore-forming and further stimulated by cellular potassium efflux. NLRC4 can specifically recognize flagellin and then trigger caspase-1 dependent pyroptosis. NODs recognize molecular pattern danger signals and build up the inflammasome.