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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. 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]

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

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 cancer, neurodegeneration and cardiovascular diseases. Some examples of pyroptosis include Salmonella-infected macrophages and abortively HIV-infected T helper cells.[5][6][7]

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 compound "pyroptosis" can 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 other forms of cell death.[9] It was suggested that microbial infection was the main evolutionary pressure for this pathway.[10] In 2013, caspase-11 dependent noncanonical pathway was discovered, suggesting lipopolysaccharide (LPS) can trigger pyroptosis and subsequent inflammatory responses independent of Toll-like receptor 4 (TLR4).[11] In 2015, gasdermin D was identified as the effector of pyroptosis that permeabilize the cell membrane[2][12].

Morphological Characteristics

Pyroptosis, as a form of programmed cell death, has many morphological differences compared to apoptosis. Both pyroptosis and apoptosis undergoes chromatin condensation, but during apoptosis, nucleus breaks into multiple chromatin bodies while in pyroptosis the nucleus remains intact.[13] The cell membrane remains intact during apoptosis. In a cell that undergoes pyroptosis, gasdermin pores are formed on the plasma membrane, resulting in water influx and cell lysis[1][14].

In terms of mechanism, pyroptosis is activated by inflammatory caspases including caspase-1/4/5 in human and caspase-11 in mice. Pro-apoptotic caspases, including caspase-6/ 7/8/9 are not required for pyroptosis. Caspase-3 activation notably, can take place in both apoptosis and pyroptosis[1][14].

Although both pyroptosis and necroptosis are triggered by membrane pore formation, pyroptosis is more controlled. Cell that undergoes pyroptosis undergoes membrane blebbing and produces protrusions termed pyroptotic bodies, which is different from necroptosis.[15] 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 the 3 forms of cell death (apoptosis, pyroptosis, and necrosis)[9][16][14]
Characteristics Apoptosis Pyroptosis Necroptosis
Morphology Cell lysis NO YES YES
Cell swelling NO YES YES
Pore formation NO YES YES
Membrane blebbing YES YES NO
DNA fragmentation YES YES YES
Nucleus intact NO YES NO
Mechanism Caspase-1 activation NO YES NO
Caspase-3 activation YES YES NO
GSDMD activation NO YES NO
Outcome Inflammation NO YES YES
Programmed cell death YES YES YES

Mechanism

Innate immune system, by using germ-line encoded pattern recognition receptors (PRRs), can recognize a wide range of pathogen-associated molecular patterns (PAMPs) and danger-associated molecular patterns (DAMPs) upon microbe infection. Classic examples of PRRs include Toll-like receptors (TLRs) and NOD-like receptors (NLRs).[17] Recognition of PAMPs and DAMPs trigger the formation of multi-protein complex inflammasomes which then activates caspases to initiate pyroptosis. The inflammasome pathway can be canonical or noncanonical with the former using caspase-1 activating inflammasomes and the latter using other caspases.[18]

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.[19] NLRP3 is activated by cellular events induced by different PAMPs and DAMPs stimuli.[20] Some non-NLR proteins like absent in melanoma 2 (AIM2) and pyrin can also be activated and form inflammasomes[18]. Also, non-inflammasome forming PRRs like TLRs, NOD1 and NOD2 are also playing important roles in pyroptosis. These receptors upregulates 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 will be released to be processed by cysteine-mediated caspase-1[21][22].

Description of the image for the visually impaired
The formation of NLRP3 inflammasome

Canonical inflammasomes mostly contain 3 components, a sensor protein (PRRs), an adaptor (ASC), and an effector (caspase-1)[18]. 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 contains a caspase activation and recruitment domain (CARD) and this homotypic CARD-CARD interactions enables autocatalytic cleavage and reassembly of procaspase-1 to form active caspase-1.[23] Alternatively, NLRC4 can directly recruit pro-caspase-1 as it has a CARD domain instead of a pyrin domain.[24]

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 10-14nm.[25] The pores allow secretion of IL-1β and IL-18 and various cytosolic content to extracellular space. These pores 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.[26]Also, GSDMD-N can only insert itself into the inner membrane with specific lipid compositions[27], which limits its damage to neighbour cells.

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 human and caspase-11 in murines. Binding of LPS onto these caspases promotes their oligomerization and activation.[28] These caspases can cleave GSDMD to release GSDMD-N and triggers pyroptosis. In addition, influx of potassium ion upon membrane permeabilization triggers activation of NLRP3, which then leads to the formation of NLRP3 inflammasome and activation of caspase-1[18]. These processes facilitate the cleavage of GSDMD and promotes the maturation and release of proinflammatory cytokines.

Overview of pyroptosis pathways

Caspase-3 dependent pyroptotic 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[2]. When apoptotic cell is not scavenged by macrophages, GSDME expression is then upregulated by p53. GSDME is then activated by caspase-3 to form pores on cell membrane. It is also found that GSDME can permeabilise mitochondrial membrane to release cytochrome c, which further activates caspase-3 and accelerates GSDME cleavage.[29] This positive feedback loop ensures programmed cell death to be carried forward.

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.[16] 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).[30] 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.[31]

Cancer

Pyroptosis, as an inflammation associated programmed cell death, has huge implications in various cancer types. Principally, pyroptosis can kill cancer cells and inhibit tumour develpment 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 microenvironment that favours tumour growth.[32] Understanding mechanisms of pyroptosis and identification of 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 inhibits 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[14].

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 caspase-1 dependent canonical pyroptosis pathway. HPV infection causes the upregulation of sirtuin 1 protein, which disrupt transcription factor for AIM2, RelB. Knockdown of sirtuin 1 upregulates AIM2 expression and triggers pyroptosis.[33]

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.[34] The condition is further accelerated by the IL-1β induced destruction of pancreatic β cell.[35]

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.[36] 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".[37]

HIV and AIDS

Recent studies demonstrate that caspase-1-mediated pyroptosis drives CD4 T-cell depletion and inflammation by HIV,[38][39] 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,[40][41] arguing that inhibition of this protein would produce beneficial rather than harmful therapeutic effects in HIV patients.

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