Pyroptosis

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Pyroptosis is a highly inflammatory form of lytic programmed cell death that occurs most frequently upon infection with intracellular pathogens and is likely to form part of the antimicrobial response. This process promotes the rapid clearance of various bacterial, viral, fungal and protozoan infections by removing intracellular replication niches and enhancing the host's defensive responses. Pyroptosis can take place in immune cells and is also reported to occur in keratinocytes and some epithelial cells. [1]

Contents

The process is initiated by formation of a large supramolecular complex termed the inflammasome (also known as a pyroptosome) upon intracellular danger signals. [2] The inflammasome activates a different set of caspases as compared to apoptosis, for example, caspase-1/4/5 in humans and caspase-11 in mice. [3] These caspases contribute to the maturation and activation of the pro-inflammatory cytokines IL-1β and IL-18, as well as the pore-forming protein gasdermin D. Formation of pores causes cell membrane rupture and release of cytokines, as well as various damage-associated molecular pattern (DAMP) molecules such as HMGB-1, ATP and DNA, out of the cell. These molecules recruit more immune cells and further perpetuate the inflammatory cascade in the tissue. [4] [5]

However, in pathogenic chronic diseases, the inflammatory response does not eradicate the primary stimulus. A chronic form of inflammation ensues that ultimately contributes to tissue damage. Pyroptosis is associated with diseases including autoinflammatory, metabolic, and cardiovascular diseases, as well as cancer and neurodegeneration. Some examples of pyroptosis include the cell death induced in Salmonella -infected macrophages and abortively HIV-infected T helper cells. [6] [7] [8]

Discovery

This type of inherently pro-inflammatory programmed cell death was named pyroptosis in 2001 by Molly Brennan and Dr. Brad T. Cookson, an associate professor of microbiology and laboratory medicine at the University of Washington. [9] The Greek pyro refers to fire and ptosis means falling. The compound term of pyroptosis may be understood as "fiery falling", which describes the bursting of pro-inflammatory chemical signals from the dying cell. Pyroptosis has a distinct morphology and mechanism compared to those of other forms of cell death. [10] It has been suggested that microbial infection was the main evolutionary pressure for this pathway. [11] Inflammasome formation was initially thought to be required for the induction of pyroptosis, but in 2013, the caspase-11 dependent noncanonical pathway was discovered, suggesting lipopolysaccharides (LPS) can trigger pyroptosis and subsequent inflammatory responses independent of toll-like receptor 4 (TLR4). [12] In 2015, gasdermin D (GSDMD) was identified as the effector of pyroptosis that forms pores in the cell membrane. [3] [13] In 2021, the high-resolution structure of the GSDMD pore was solved by cryo-electron microscopy (cryo-EM). [14] Also in 2021, an additional molecule, NINJ1, was found to be required for the plasma membrane rupture during pyroptosis. [15]

Morphological characteristics

Pyroptosis, as a form of programmed cell death, has many morphological differences as compared to apoptosis. Both pyroptosis and apoptosis undergo chromatin condensation, but during apoptosis, the nucleus breaks into multiple chromatin bodies; in pyroptosis, the nucleus remains intact. [16] In a cell that undergoes pyroptosis, gasdermin pores are formed on the plasma membrane, resulting in water influx. [1] [17]

In terms of mechanism, pyroptosis is activated by inflammatory caspases, including caspase-1/4/5 in humans and caspase-11 in mice. Caspase-8 can act as an upstream regulator of inflammasome activation in context-dependent manners. [18] Caspase-3 activation can take place in both apoptosis and pyroptosis. [1] [17]

Although both pyroptosis and necroptosis are triggered by membrane pore formation, pyroptosis is more controlled. Cells that undergo pyroptosis exhibit membrane blebbing and produce protrusions known as pyroptotic bodies, a process not found in necroptosis. [19] Also, necroptosis works in a caspase-independent fashion. It is proposed that both pyroptosis and necroptosis may act as defence systems against pathogens when apoptotic pathways are blocked.

Summary of the different morphologies, mechanisms and outcomes of three most well-characterized forms of cell death (apoptosis, pyroptosis, and necrosis) [10] [6] [17]
CharacteristicsApoptosisPyroptosisNecroptosis
MorphologyCell lysisNOYESYES
Cell swellingNOYESYES
Pore formationNOYESYES
Membrane blebbingYESYESNO
DNA fragmentationYESYESYES
Nucleus intactNOYESNO
Mechanism Caspase-1 activationNOYESNO
Caspase-3 activationYESYESNO
GSDMD activationNOYESNO
OutcomeInflammationNOYESYES
Programmed cell deathYESYESYES

Mechanism

The innate immune system, by using germ-line encoded pattern recognition receptors (PRRs), can recognize a wide range of pathogen-associated molecular patterns (PAMPs) and damage-associated molecular patterns (DAMPs) upon microbe infection. Classic examples of PRRs include toll-like receptors (TLRs) and NOD-like receptors (NLRs). [20] Recognition of PAMPs and DAMPs triggers the formation of multi-protein complex inflammasomes, which then activates caspases to initiate pyroptosis. The inflammasome pathway may be canonical or noncanonical, with the former using caspase-1-activating inflammasomes and the latter using other caspases. [21]

The canonical inflammasome pathway

In the canonical inflammasome pathway, PAMPs and DAMPs are recognised by certain endogenous PRRs. For example, NLR proteins NLRC4 can recognise flagellin and type III secretion system components. [22] NLRP3 is activated by cellular events induced by different PAMPs and DAMPs stimuli. [23] Some non-NLR proteins like absent in melanoma 2 (AIM2) and pyrin can also be activated and form inflammasomes. [21] Also, non-inflammasome-forming PRRs such as TLRs, NOD1 and NOD2 also play important roles in pyroptosis. These receptors upregulate expression of inflammatory cytokines such as IFN α/β, tumour necrosis factor (TNF), IL-6 and IL-12 through NF-κB and MAPK-signaling pathways. In addition, pro-IL-1β and pro-IL-18 are released to be processed by cysteine-mediated caspase-1. [24] [25]

The formation of NLRP3 inflammasome Inflammasome final1.png
The formation of NLRP3 inflammasome

Canonical inflammasomes mostly contain three components: a sensor protein (PRRs), an adaptor (ASC) and an effector (caspase-1). [21] Generally, inflammasome-forming NLR proteins share a similar structure, several leucine-rich repeat (LRR) domains, a central nucleotide-binding and oligomerization domain (NBD) and an N-terminal pyrin domain (PYD). NLRP3, for example, recruits ASC adaptor protein via PYD-PYD interaction. Both pro-caspase-1 and ASC contain a caspase activation and recruitment domain (CARD), and this homotypic CARD-CARD interaction enables autocatalytic cleavage and reassembly of procaspase-1 to form active caspase-1. [26] Alternatively, NLRC4 can directly recruit pro-caspase-1, as it has a CARD instead of a PYD. [27] In addition to their formation as a complex to induce pyroptosis, inflammasomes can also be integral components of larger cell death-inducing complexes called PANoptosomes to induce PANoptosis, another inflammatory form of cell death.

Activated caspase-1 is responsible for cleavage of pro-IL-1β and pro-IL-18. These cytokines, once processed, will be in their biologically active form ready to be released from the host cells. In addition, caspase-1 also cleaves the cytosolic gasdermin D (GSDMD). GSDMD can be cleaved to produce an N-terminal domain (GSDMD-N) and a C-terminal domain (GSDMD-C). GSDMD-N can oligomerize and form transmembrane pores that have an inner diameter of 10-14 nm. [28] The pores allow secretion of IL-1β and IL-18 and various cytosolic content to extracellular space, and they also disrupt the cellular ionic gradient. The resulting increase in osmotic pressure causes an influx of water followed by cell swelling and bursting. Notably, GSDMD-N is autoinhibited by GSDMD C-terminal domain before cleavage to prevent cell lysis in normal conditions. [29] Also, GSDMD-N can only insert itself into the inner membrane with specific lipid compositions, [30] which limits its damage to neighbour cells. Downstream of GSDMD, NINJ1 is now thought to be required for the plasma membrane rupture during pyroptosis. [15]

The noncanonical inflammasome pathway

The noncanonical inflammasome pathway is initiated by binding of lipopolysaccharide (LPS) of gram-negative bacteria directly onto caspase-4/5 in humans and caspase-11 in murines. Binding of LPS onto these caspases promotes their oligomerization and activation. [12] These caspases can cleave GSDMD to release GSDMD-N and trigger pyroptosis. In addition, an influx of potassium ions upon membrane permeabilization triggers activation of NLRP3, which then leads to formation of NLRP3 inflammasome and activation of caspase-1. [21] These processes facilitate the cleavage of GSDMD and promote the maturation and release of pro-inflammatory cytokines.

Overview of pyroptosis pathways Pyroptosis pathways 2.png
Overview of pyroptosis pathways

Caspase-3-dependent cell death pathway

An alternative pathway that links apoptosis and pyroptosis has been recently proposed. Caspase-3, an executioner caspase in apoptosis, can cleave gasdermin E (GSDME) to produce a N-terminal fragment and a C-terminal fragment in a way similar to GSDMD cleavage. [3] When apoptotic cells are not scavenged by macrophages, GSDME expression is then upregulated by p53. GSDME is then activated by caspase-3 to form pores on the cell membrane. It has also been found that GSDME can permeabilise mitochondrial membranes to release cytochrome c, which further activates caspase-3 and accelerates GSDME cleavage. [31] This positive feedback loop ensures that programmed cell death is carried forward.

Clinical relevance

Infection

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 by introducing cell death to restrict pathogen growth. [6] 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.) [32] 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 is detrimental. If the amplification cycles persist, metabolic disorder, autoinflammatory diseases and liver injury associated with chronic inflammation will occur. [32]

Recently, pyroptosis and downstream pathways were identified as promising targets for treatment of severe COVID-19-associated diseases. [33]

Cerebrovascular disease

Recent studies show that pyroptosis plays a role in the pathophysiology of intracerebral hemorrhage, and mitigating pyroptosis could be an intervention strategy to inhibit the inflammatory response after intracerebral hemorrhage. [34]

Cancer

Pyroptosis, as an inflammation-associated programmed cell death, has wide implications in various cancer types. Principally, pyroptosis can kill cancer cells and inhibit tumour development in the presence of endogenous DAMPs. In some cases, GSDMD can be used as a prognostic marker for cancers. However, prolonged production of inflammatory bodies may facilitate the formation of microenvironments that favour tumour growth. [35] Understanding the mechanisms of pyroptosis and identifying pyroptosis-associated molecules can be useful in treating different cancers.

In gastric cancer cells, presence of GSDMD can inhibit cyclin A2/CDK2 complexes, leading to cell cycle arrest and thus inhibit tumour development. Also, cellular concentration of GSDME increases when gastric cancer cells are treated with certain chemotherapy drugs. GSDME then activates caspase-3 and triggers pyroptotic cell death. [17]

Cervical cancer can be caused by human papillomavirus (HPV) infection. AIM2 protein can recognise viral DNA in cytoplasm and form AIM2 inflammasome, which then triggers by a caspase-1 dependent canonical pyroptosis pathway. HPV infection causes the upregulation of sirtuin 1 protein, which disrupts the transcription factor for AIM2, RelB. Knockdown of sirtuin 1 upregulates AIM2 expression and triggers pyroptosis. [36]

Metabolic disorder

The level of expression of NLRP3 inflammasome and caspase-1 has a direct relation to 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 impair 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. [37] The condition is further accelerated by the IL-1β-induced destruction of pancreatic β cells. [38]

Cryopyrinopathies

A mutation in the gene coding of inflammasomes leads to a group of autoinflammatory diseases 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. [39] The mutated gene in such cases is the NLRP3, impeding the activation of inflammasome and resulting in an excessive production of IL-1β. This effect is known as "gain-of-function". [40]

HIV and AIDS

Recent studies demonstrate that caspase-1-mediated pyroptosis drives CD4 T-cell depletion and inflammation by HIV, [7] [41] [42] [43] 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, [44] [45] arguing that inhibition of this protein would produce beneficial rather than harmful therapeutic effects in HIV patients.

Related Research Articles

<span class="mw-page-title-main">Caspase</span> Family of cysteine proteases

Caspases are a family of protease enzymes playing essential roles in programmed cell death. 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 12 confirmed caspases in humans and 10 in mice, carrying out a variety of cellular functions.

<span class="mw-page-title-main">Itaconic acid</span> Chemical compound

Itaconic acid (also termed methylidenesuccinic acid and 2-methylidenebutanedioic acid) is a fatty acid containing five carbons (carbon notated as C), two of which are in carboxyl groups (notated as -CO2H) and two others which are double bonded together (i.e., C=C). (itaconic acid's chemical formula is C5H6O4, see adjacent figure and dicarboxylic acids). At the strongly acidic pH levels below 2, itaconic acid is electrically neutral because both of its carboxy residues are bound to hydrogen (notated as H); at the basic pH levels above 7, it is double negatively charged because both of its carboxy residues are not bound to H, i.e., CO2 (its chemical formula is C5H4O42-); and at acidic pH's between 2 and 7, it exists as a mixture with none, one, or both of its carboxy residues bound to hydrogen. In the cells and most fluids of living animals, which generally have pH levels above 7, itaconic acid exists almost exclusively in its double negatively charged form; this form of itaconic acid is termed itaconate. Itaconic acid and itaconate exist as cis and trans isomers (see cis–trans isomerism). Cis-itaconic acid and cis-itaconate isomers have two H's bound to one carbon and two residues (noted as R) bound to the other carbon in the double bound (i.e., H2C=CR2) whereas trans-itaconic acid and trans-itaconate have one H and one R residue bound to each carbon of the double bound. The adjacent figure shows the cis form of itaconic acid. Cis-aconitic acid spontaneously converts to its thermodynamically more stable (see chemical stability) isomer, trans-aconitic acid, at pH levels below 7. The medical literature commonly uses the terms itaconic acid and itaconate without identifying them as their cis isomers. This practice is used here, i.e., itaconic acid and itaconate refer to their cis isomers while the trans isomer of itaconate (which has been detected in fungi but not animals) is here termed trans-itaconate (trans-itaconic acid is not further mentioned here).

<span class="mw-page-title-main">Interleukin 1 beta</span> Mammalian protein found in Homo sapiens

Interleukin-1 beta (IL-1β) also known as leukocytic pyrogen, leukocytic endogenous mediator, mononuclear cell factor, lymphocyte activating factor and other names, is a cytokine protein that in humans is encoded by the IL1B gene. There are two genes for interleukin-1 (IL-1): IL-1 alpha and IL-1 beta. IL-1β precursor is cleaved by cytosolic caspase 1 to form mature IL-1β.

<span class="mw-page-title-main">Caspase 1</span> Protein-coding gene in the species Homo sapiens

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.

<span class="mw-page-title-main">NLRP3</span> Human protein and coding gene

NLR family pyrin domain containing 3 (NLRP3), is a protein that in humans is encoded by the NLRP3 gene located on the long arm of chromosome 1.

<span class="mw-page-title-main">NLRP12</span> Protein-coding gene in the species Homo sapiens

Nucleotide-binding oligomerization domain-like receptor (NLR) pyrin domain (PYD)-containing protein 12 is a protein that in humans is encoded by the NLRP12 gene.

<span class="mw-page-title-main">AIM2</span> Protein-coding gene in the species Homo sapiens

Interferon-inducible protein AIM2 also known as absent in melanoma 2 or simply AIM2 is a protein that in humans is encoded by the AIM2 gene.

Inflammasomes are cytosolic multiprotein complexes of the innate immune system responsible for the activation of inflammatory responses and cell death. They are formed as a result of specific cytosolic pattern recognition receptors (PRRs) sensing microbe-derived pathogen-associated molecular patterns (PAMPs), damage-associated molecular patterns (DAMPs) from the host cell, or homeostatic disruptions. Activation and assembly of the inflammasome promotes the activation of caspase-1, which then proteolytically cleaves pro-inflammatory cytokines, interleukin 1β (IL-1β) and interleukin 18 (IL-18), as well as the pore-forming molecule gasdermin D (GSDMD). The N-terminal GSDMD fragment resulting from this cleavage induces a pro-inflammatory form of programmed cell death distinct from apoptosis, referred to as pyroptosis, which is responsible for the release of mature cytokines. Additionally, inflammasomes can act as integral components of larger cell death-inducing complexes called PANoptosomes, which drive another distinct form of pro-inflammatory cell death called PANoptosis.

<span class="mw-page-title-main">Pyrin domain</span>

A pyrin domain is a protein domain and a subclass of protein motif known as the death fold, the 4th and most recently discovered member of the death domain superfamily (DDF). It was originally discovered in the pyrin protein, or marenostrin, encoded by MEFV. The mutation of the MEFV gene is the cause of the disease known as Familial Mediterranean Fever. The domain is encoded in 23 human proteins and at least 31 mouse genes.

<span class="mw-page-title-main">NLRP11</span> Protein-coding gene in the species Homo sapiens

NOD-like receptor family pyrin domain containing 11 is a protein that in humans is encoded by the NLRP11 gene located on the long arm of human chromosome 19q13.42. NLRP11 belongs to the NALP subfamily, part of a large subfamily of CATERPILLER. It is also known as NALP11, PYPAF6, NOD17, PAN10, and CLR19.6

NLRP (Nucleotide-binding oligomerization domain, Leucine rich Repeat and Pyrin domain containing), also abbreviated as NALP, is a type of NOD-like receptor. NOD-like receptors are a type of pattern recognition receptor that are found in the cytosol of the cell, recognizing signals of antigens in the cell. NLRP proteins are part of the innate immune system and detect conserved pathogen characteristics, or pathogen-associated molecular patterns, such as such as peptidoglycan, which is found on some bacterial cells. It is thought that NLRP proteins sense danger signals linked to microbial products, initiating the processes associated with the activation of the inflammasome, including K+ efflux and caspase 1 activation. NLRPs are also known to be associated with a number of diseases. Research suggests NLRP proteins may be involved in combating retroviruses in gametes. As of now, there are at least 14 different known NLRP genes in humans, which are named NLRP1 through NLRP14. The genes translate into proteins with differing lengths of leucine-rich repeat domains.

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.

Immunogenic cell death is any type of cell death eliciting an immune response. Both accidental cell death and regulated cell death can result in immune response. Immunogenic cell death contrasts to forms of cell death that do not elicit any response or even mediate immune tolerance.

<span class="mw-page-title-main">GSDMD</span> Protein found in humans

Gasdermin D 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 vertebrates and comprises six members in humans, GSDMA, GSDMB, GSDMC, GSDMD, GSDME (DFNA5) and DFNB59 (Pejvakin). Members of the gasdermin family are expressed in a variety of cell types including epithelial cells and immune cells. GSDMA, GSDMB, GSDMC, GSDMD and GSDME have been suggested to act as tumour suppressors.

<span class="mw-page-title-main">Thirumala-Devi Kanneganti</span> Indian immunologist

Thirumala-Devi Kanneganti is an immunologist and is the Rose Marie Thomas Endowed Chair, Vice Chair of the Department of Immunology, and Member at St. Jude Children's Research Hospital. She is also Director of the Center of Excellence in Innate Immunity and Inflammation at St. Jude Children's Research Hospital. Her research interests include investigating fundamental mechanisms of innate immunity, including inflammasomes and inflammatory cell death, PANoptosis, in infectious and inflammatory disease and cancer.

<span class="mw-page-title-main">Vishva Dixit</span> Kenyan molecular biologist

Vishva Mitra Dixit is a physician of Indian origin who is currently Vice President and Senior Fellow of Physiological Chemistry and Research Biology at Genentech.

<span class="mw-page-title-main">Dapansutrile</span> Chemical compound

Dapansutrile (OLT1177) is an inhibitor of the NLRP3 inflammasome.

Autoinflammatory diseases (AIDs) are a group of rare disorders caused by dysfunction of the innate immune system. These responses are characterized by periodic or chronic systemic inflammation, usually without the involvement of adaptive immunity.

PANoptosis is a unique, innate immune, inflammatory, and lytic cell death pathway driven by caspases and RIPKs and regulated by multiprotein PANoptosome complexes. The assembly of the PANoptosome cell death complex occurs in response to germline-encoded pattern-recognition receptors (PRRs) sensing pathogens, including bacterial, viral, and fungal infections, as well as pathogen-associated molecular patterns, damage-associated molecular patterns, and cytokines that are released during infections, inflammatory conditions, and cancer. Several PANoptosome complexes, such as the ZBP1-, AIM2-, RIPK1-, and NLRP12-PANoptosomes, have been characterized so far.

Jonathan C. Kagan is an American immunologist and the Marian R. Neutra, Ph.D. Professor of Pediatrics at Harvard Medical School. He is also the director of Basic Research and Shwachman Chair in Gastroenterology at Boston Children's Hospital. Kagan is a world leader in defining the molecular basis of innate immunity and inflammation.

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