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[1] and abortively HIV-infected T helper cells.[2][3]

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.[4] Caspase-1 is activated during pyroptosis by a large supramolecular complex termed the pyroptosome (also known as an inflammasome).[5] 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.[6][7] 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.

Discovery

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.[8] 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.[9] It was suggested that microbial infection was the main evolutionary pressure for this pathway.[10]

Molecular mechanism and morphology

Pyroptosis mechanism
The signaling pathway of pyroptosis upon recognition of 'danger' signals

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).[11] 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.[12] 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.[13]

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.[14] 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.[15] Moreover, DNA cleavage with retained integrity and nuclear condensation has also been found to be associated with the process.

Summary of the different morphologies, mechanisms, and outcomes of the 3 forms of cell death (apoptosis, pyroptosis, and necrosis)[9][14]
Characteristics Apoptosis Pyroptosis Necrosis
Morphology Cell lysis NO YES YES
Cell swelling NO YES YES
Pore formation NO YES YES
Membrane blebbing YES NO NO
DNA fragmentation YES YES YES
Mechanism Caspase-1 NO YES NO
Caspase-3 YES NO NO
Cytochome-c release YES NO NO
Outcome Inflammation NO(anti) YES YES
Programmed cell death YES YES NO

Factors that are involved in the pathway

TLRs

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.[16]

NLRs

NOD-like receptors (NLRs) consist of more than 20 subsets,[17] including NOD1 and NOD2, NLRP3 (also known as NALP3), NLRC4.[18] 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.[19] 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.[11] NODs recognize molecular pattern danger signals and build up the inflammasome.

Inflammasome final1
The formation of NLRP3 inflammasome

Inflammasome

The formation of the multi-protein complex inflammasome is achieved through the binding of intracellular bacterial, viral or host danger signals to the NLRs receptor, whose assembly leads to the activation of caspase-1[20] that is required in the processing and secretion of the pro-inflammatory cytokines. The best characterized inflammasome complex, NLRP3, has 3 distinct domains: several leucine-rich repeat (LRR) domains, a central nucleotide-binding and oligomerization domain (NBD) and an N-terminal pyrin domain (PYD).[17][19] The interaction between NLRP3 and caspase-1 is via the adaptor protein ASC. ASC contains a caspase activation and recruitment domain (CARD) that binds and facilitates activation of pro-caspase-1 through CARD-CARD interactions.[17] In some cases, NLRC4 can directly recruit caspase-1 as it has a CARD domain.

Caspase-1 activation

The crucial enzyme required in the stimulation of the downstream pathway is caspase-1, which is located inside the cells. Caspase-1 was known as an interleukin-1β converting enzyme, as it was first discovered in association with the cleavage of pro-IL-1β.[14][21] The pro-caspase-1 with a 10-kDa CARD domain[22] will be recruited by various inflammasome. Similar to other caspases, caspase-1 starts off as an inactive precursor called zymogen. The caspase-1 enzymes become activated when they oligomerize and form tetramers. This process is spontaneous due to the fact that everything in the inflammasome is in close proximity with each other.[22] The cysteine-cleaved enzyme will not only cause cell death but is also responsible for the cleavage of the pro-inflammatory cytokines IL-1β and IL-18. The cytokines, once processed, will be in their biologically active form ready to be released from the host cells. The development of efficient adaptive immune responses depends on the recruitment and activation of the immune cells by inflammatory cytokines.

Clinical relevance

Pyroptosis acts as a defence mechanism against infection by inducing pathological inflammation. The formation of inflammasomes and the activity of caspase-1 determine the balance between pathogen resolution and disease.

In a healthy cell, caspase-1 activation helps to fight infection caused by Salmonella and Shigella via introducing cell death to restrict pathogen growth.[14] When the ‘danger' signal is sensed, the quiescent cells will be activated to undergo pyroptosis and produce inflammatory cytokines IL-1β and IL-18. IL-18 will stimulate IFNγ production and initiates the development of TH1 responses. (TH1 responses tend to release cytokines that direct an immediate removal of the pathogen).[23] The cell activation results in an increase in cytokine levels, which will augment the consequences of inflammation and this, in turn, contributes to the development of the adaptive response as infection progresses. The ultimate resolution will clear pathogens.

In contrast, persistent inflammation will produce excessive immune cells which will be detrimental. If the amplification cycles persist, metabolic disorder, autoinflammatory diseases and liver injury associated with chronic inflammation will take place.[24]

Metabolic disorder

The level of expression of NLRP3 inflammasome and caspase-1 has direct relation with the severity of several metabolic syndromes, such as obesity and type II diabetic mellitus (T2DM). This is because the subsequent production level of IL-1β and IL-18, cytokines that impairs the secretion of insulin, is affected by the activity of caspase-1. Glucose uptake level is then diminished, and the condition is known as insulin resistance.[25] The condition is further accelerated by the IL-1β induced destruction of pancreatic β cell.[26]

Cryopyrinopathies

A mutation in the gene coding of inflammasome leads to a group of autoinflammatory disease called cryopyrinopathies. This group includes Muckle–Wells syndrome, cold autoinflammatory syndrome, and chronic infantile neurologic cutaneous and articular syndrome, all showing symptoms of sudden fevers and localized inflammation.[27] The mutated gene in this case is the NLRP3, impeding the activation of inflammasome, resulting in an excessive production IL-1β. This effect is known as "gain-of-function".[28]

HIV and AIDS

Recent studies demonstrate that caspase-1-mediated pyroptosis drives CD4 T-cell depletion and inflammation by HIV,[29][30] two signature events that propel HIV disease progression to AIDS. Although pyroptosis contributes to the host's ability to rapidly limit and clear infection by removing intracellular replication niches and enhancing defensive responses through the release of proinflammatory cytokines and endogenous danger signals, in pathogenic inflammation, such as that elicited by HIV-1, this beneficial response does not eradicate the primary stimulus. In fact, it appears to create a pathogenic vicious cycle in which dying CD4 T cells release inflammatory signals that attract more cells into the infected lymphoid tissues to die and to produce chronic inflammation and tissue injury. It may be possible to break this pathogenic cycle with safe and effective caspase-1 inhibitors. These agents could form a new and exciting ‘anti-AIDS' therapy for HIV-infected subjects in which the treatment targets the host instead of the virus. Of note, Caspase-1 deficient mice develop normally,[31][32] arguing that inhibition of this protein would produce beneficial rather than harmful therapeutic effects in HIV patients.

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Caspase

Caspases (cysteine-aspartic proteases, cysteine aspartases or cysteine-dependent aspartate-directed proteases) are a family of protease enzymes playing essential roles in programmed cell death (including apoptosis, pyroptosis and necroptosis) and inflammation. They are named caspases due to their specific cysteine protease activity – a cysteine in its active site nucleophilically attacks and cleaves a target protein only after an aspartic acid residue. As of 2009, there are 11 or 12 confirmed caspases in humans and 10 in mice, carrying out a variety of cellular functions.

The role of these enzymes in programmed cell death was first identified in 1993, with their functions in apoptosis well characterised. This is a form of programmed cell death, occurring widely during development, and throughout life to maintain cell homeostasis. Activation of caspases ensures that the cellular components are degraded in a controlled manner, carrying out cell death with minimal effect on surrounding tissues.Caspases have other identified roles in programmed cell death such as pyroptosis and necroptosis. These forms of cell death are important for protecting an organism from stress signals and pathogenic attack. Caspases also have a role in inflammation, whereby it directly processes pro-inflammatory cytokines such as pro-IL1β. These are signalling molecules that allow recruitment of immune cells to an infected cell or tissue. There are other identified roles of caspases such as cell proliferation, tumour suppression, cell differentiation, neural development and axon guidance and ageing.Caspase deficiency has been identified as a cause of tumour development. Tumour growth can occur by a combination of factors, including a mutation in a cell cycle gene which removes the restraints on cell growth, combined with mutations in apoptopic proteins such as Caspases that would respond by inducing cell death in abnormally growing cells. Conversely, over-activation of some caspases such as caspase-3 can lead to excessive programmed cell death. This is seen in several neurodegenerative diseases where neural cells are lost, such as Alzheimer's disease. Caspases involved with processing inflammatory signals are also implicated in disease. Insufficient activation of these caspases can increase an organism's susceptibility to infection, as an appropriate immune response may not be activated. The integral role caspases play in cell death and disease has led to research on using caspases as a drug target. For example, inflammatory caspase-1 has been implicated in causing autoimmune diseases; drugs blocking the activation of Caspase-1 have been used to improve the health of patients. Additionally, scientists have used caspases as cancer therapy to kill unwanted cells in tumours.

Caspase 1

Caspase-1/Interleukin-1 converting enzyme (ICE) is an evolutionarily conserved enzyme that proteolytically cleaves other proteins, such as the precursors of the inflammatory cytokines interleukin 1β and interleukin 18 as well as the pyroptosis inducer Gasdermin D, into active mature peptides. It plays a central role in cell immunity as an inflammatory response initiator. Once activated through formation of an inflammasome complex, it initiates a proinflammatory response through the cleavage and thus activation of the two inflammatory cytokines, interleukin 1β (IL-1β) and interleukin 18 (IL-18) as well as pyroptosis, a programmed lytic cell death pathway, through cleavage of Gasdermin D. The two inflammatory cytokines activated by Caspase-1 are excreted from the cell to further induce the inflammatory response in neighboring cells.

Caspase 11

Murine caspase-11, and its human homologs caspase-4 and caspase-5, are mammalian intracellular receptor proteases activated by TLR4 and TLR3 signaling during the innate immune response. Caspase-11, also termed the non-canonical inflammasome, is activated by TLR3/TLR4-TRIF signaling and directly binds cytosolic lipopolysaccharide (LPS), a major structural element of Gram-negative bacterial cell walls. Activation of caspase-11 by LPS is known to cause the activation of other caspase proteins, leading to septic shock, pyroptosis, and often organismal death.

Cell death

Cell death is the event of a biological cell ceasing to carry out its functions. This may be the result of the natural process of old cells dying and being replaced by new ones, or may result from such factors as disease, localized injury, or the death of the organism of which the cells are part. Apoptosis or Type I cell-death, and autophagy or Type II cell-death are both forms of programmed cell death, while necrosis is a non-physiological process that occurs as a result of infection or injury.

Dead on arrival

Dead on arrival (DOA), also dead in the field and brought in dead (BID), indicates that a patient was found to be already clinically dead upon the arrival of professional medical assistance, often in the form of first responders such as emergency medical technicians, paramedics, or police.

In some jurisdictions, first responders must consult verbally with a physician before officially pronouncing a patient deceased, but once cardiopulmonary resuscitation is initiated, it must be continued until a physician can pronounce the patient dead.

Death messenger

Death messengers, in former times, were those who were dispatched to spread the news that an inhabitant of their city or village had died. They were to wear unadorned black and go door to door with the message, "You are asked to attend the funeral of the departed __________ at (time, date, and place)." This was all they were allowed to say, and were to move on to the next house immediately after uttering the announcement. This tradition persisted in some areas to as late as the mid-19th century.

Death rattle

Terminal respiratory secretions (or simply terminal secretions), known colloquially as a death rattle, are sounds often produced by someone who is near death as a result of fluids such as saliva and bronchial secretions accumulating in the throat and upper chest. Those who are dying may lose their ability to swallow and may have increased production of bronchial secretions, resulting in such an accumulation. Usually, two or three days earlier, the symptoms of approaching death can be observed as saliva accumulates in the throat, making it very difficult to take even a spoonful of water. Related symptoms can include shortness of breath and rapid chest movement. While death rattle is a strong indication that someone is near death, it can also be produced by other problems that cause interference with the swallowing reflex, such as brain injuries.It is sometimes misinterpreted as the sound of the person choking to death, or alternatively, that they are gargling.

Dignified death

Dignified death is a somewhat elusive concept often related to suicide. One factor that has been cited as a core component of dignified death is maintaining a sense of control. Another view is that a truly dignified death is an extension of a dignified life. There is some concern that assisted suicide does not guarantee a dignified death, since some patients may experience complications such as nausea and vomiting. There is some concern that age discrimination denies the elderly a dignified death.

Dysthanasia

In medicine, dysthanasia means "bad death" and is considered a common fault of modern medicine.Dysthanasia occurs when a person who is dying has their biological life extended through technological means without regard to the person's quality of life. Technologies such as an implantable cardioverter defibrillator, artificial ventilation, ventricular assist devices, and extracorporeal membrane oxygenation can extend the dying process.

Dysthanasia is a term generally used when a person is seen to be kept alive artificially in a condition where, otherwise, they cannot survive; sometimes for some sort of ulterior motive. The term was used frequently in the investigation into the death of Formula One driver Ayrton Senna in 1994.

GSDMD

Gasdermin D (GSDMD) is a protein that in humans is encoded by the GSDMD gene on chromosome 8.

It belongs to the gasdermin family which is conserved among all vertebrates and comprises six members, GSDMA, GSDMB, GSDMC, GSDMD, DFNA5 and DFNB59. Members of the gasdermin family are mainly expressed in epithelial tissues and appear to play a role in regulation of epithelial proliferation and differentiation. GSDMA, GSDMC, GSDMD and DFNA5 have been suggested to act as tumour suppressors.

IFI16

Gamma-interferon-inducible protein Ifi-16 (Ifi-16) also known as interferon-inducible myeloid differentiation transcriptional activator is a protein that in humans is encoded by the IFI16 gene.

Inflammasome

The inflammasome is a multiprotein oligomer responsible for the activation of inflammatory responses. The inflammasome promotes the maturation and secretion of pro-inflammatory cytokines interleukin 1β (IL-1β) and interleukin 18 (IL-18). The secretion of these cytokines results in pyroptosis, a form of programmed pro-inflammatory cell death distinct from apoptosis. In the case of dysregulation of the inflammasome, an assortment of major diseases may arise. It is expressed in myeloid cells and is a component of the innate immune system. The inflammasome complex can consist of caspase 1, PYCARD, NALP and sometimes caspase 5 (also known as caspase 11 or ICH-3). NLRs (nucleotide-binding oligomerization domain and leucine-rich repeat-containing receptors) and ALRs (AIM2-like receptors) can also form an inflammasome. The exact composition of an inflammasome depends on the activator which initiates inflammasome assembly, e.g. dsRNA will trigger one inflammasome composition whereas asbestos will assemble a different variant. Because the pro-inflammatory pathway does not need Toll-like receptors (TLRs), inflammasomes with AIM2 can detect cytoplasmic DNA, a danger signal, that may be threatening and strengthen their innate response.

Lazarus sign

The Lazarus sign or Lazarus reflex is a reflex movement in brain-dead or brainstem failure patients, which causes them to briefly raise their arms and drop them crossed on their chests (in a position similar to some Egyptian mummies). The phenomenon is named after the Biblical figure Lazarus of Bethany, whom Jesus raised from the dead in the Gospel of John.

Megadeath

Megadeath (or megacorpse) is one million human deaths, usually caused by a nuclear explosion. The term was used by scientists and thinkers who strategized likely outcomes of all-out nuclear warfare.

Necronym

A necronym (from the Greek words νεκρός, nekros, "dead" and ὄνομα ónoma, "name") is a reference to, or name of, a person who has died. Many cultures have taboos and traditions associated with referring to such a person. These vary from the extreme of never again speaking the person's real name, often using some circumlocution instead, to the opposite extreme of commemorating it incessantly by naming other things or people after the deceased.

For instance, in some cultures it is common for a newborn child to receive the name (a necronym) of a relative who has recently died, while in others to reuse such a name would be considered extremely inappropriate or even forbidden. While this varies from culture to culture, the use of necronyms is quite common.

Obituary

An obituary (obit for short) is a news article that reports the recent death of a person, typically along with an account of the person's life and information about the upcoming funeral. In large cities and larger newspapers, obituaries are written only for people considered significant. In local newspapers, an obituary may be published for any local resident upon death. A necrology is a register or list of records of the deaths of people related to a particular organization, group or field, which may only contain the sparsest details, or small obituaries. Historical necrologies can be important sources of information.

Two types of paid advertisements are related to obituaries. One, known as a death notice, omits most biographical details and may be a legally required public notice under some circumstances. The other type, a paid memorial advertisement, is usually written by family members or friends, perhaps with assistance from a funeral home. Both types of paid advertisements are usually run as classified advertisements.

Pallor mortis

Pallor mortis (Latin: pallor "paleness", mortis "of death"), the first stage of death, is an after-death paleness that occurs in those with light/white skin.

Pathophysiology of HIV/AIDS

HIV is commonly transmitted via unprotected sexual activity, blood transfusions, hypodermic needles, and from mother to child. Upon acquisition of the virus, the virus replicates inside and kills T helper cells, which are required for almost all adaptive immune responses. There is an initial period of influenza-like illness, and then a latent, asymptomatic phase. When the CD4 lymphocyte count falls below 200 cells/ml of blood, the HIV host has progressed to AIDS, a condition characterized by deficiency in cell-mediated immunity and the resulting increased susceptibility to opportunistic infections and certain forms of cancer.

Post-mortem interval

Post-mortem interval (PMI) is the time that has elapsed since a person has died. If the time in question is not known, a number of medical/scientific techniques are used to determine it. This also can refer to the stage of decomposition of the body.

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