What is Pyroptosis?

Pyroptosis is a pro-inflammatory form of programmed cell death characterized by cell swelling, membrane rupture, and the release of pro-inflammatory cytokines.

Unlike apoptosis, which mainly helps maintain tissue homeostasis and prevents inflammation, pyroptosis promotes an inflammatory response to eliminate damaged cells.

Pyroptosis is generally triggered by the activation of different caspases, most commonly caspase-1 and caspase-11, which cleave proteins called gasdermins.

The main pathways include the canonical inflammasome pathway, non-canonical pathway, caspase 3/8 pathway, and granzyme-mediated pathway.

Excessive activation of pyroptosis is associated with several diseases, particularly cancer, autoinflammatory disorders, and neurodegenerative diseases, as it leads to inflammation and tissue damage.

The NLRP3 inflammasome is activated in microglia and neurons by amyloid-beta aggregates, neurofibrillary tangles in AD, and misfolded α-synuclein in PD. This activation leads to the cleavage of GSDMD and subsequent pyroptosis, contributing to neuroinflammation.

Yes, there is potential for developing therapeutic strategies that target specific pyroptosis pathways to treat inflammatory diseases and cancer. Potential therapies include gasdermin activators and inhibitors.

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Alpha-Synuclein: a presynaptic neuronal protein that is genetically and neuropathologically associated with Parkinson's disease (PD).

Alzheimer's Disease: a progressive neurodegenerative disorder characterized by cognitive decline, memory loss, and behavioral changes. It is associated with the accumulation of amyloid-beta plaques and tau tangles in the brain, and loss of neurons and synapses in the cerebral cortex and subcortical regions.

Amyloid-Beta (Aβ): a peptide derived from the amyloid precursor protein (APP) that can aggregate to form plaques.

Apoptosis: a non-inflammatory, programmed cell death mediated by caspases 2, 8, 9, 10, 11, and 12. This process leads to a disassembly of the cell characterized by cell shrinkage, DNA fragmentation, and nuclear condensation. The cellular components are then packaged into apoptotic bodies for removal.

ASC: an adaptor protein containing a PYD and CARD domain, which mediates the recruitment of pro-caspase-1 to sensor proteins like NLRs during inflammasome assembly. This interaction enables caspase-1 activation and subsequent initiation of inflammatory signaling pathways, including cytokine processing and pyroptosis.

Biomarker: a measurable indicator of a biological state or condition. Biomarkers are often used in medicine and research to detect or monitor the presence, progress, or severity of a disease, as well as to assess the effectiveness of a treatment.

Blood-Brain Barrier (BBB) Permeability: BBB is a highly selective semipermeable layer of endothelial cells between the circulatory system and the brain. This layer forms a barrier that protects the brain from harmful or unwanted substances in the blood. Increased BBB permeability can result from neurological diseases and traumatic injuries and can be visible with gadolinium scans. Increased BBB permeability is a key factor in MS lesion formation, allowing immune cells to enter the brain and cause inflammation.

Caspase-1: an inflammatory cysteine protease activated within multiprotein complexes called inflammasomes. It executes pyroptosis by cleaving gasdermin D (GSDMD) and processes pro-inflammatory cytokines pro-IL-1β and pro-IL-18 into their active forms to drive inflammation.

Cytokine: a protein that serves as a signalling molecule among immune system cells. Cytokines are classified into interleukins, interferons, tumour necrosis factors (TNF), chemokines, colony-stimulating factors, and transforming growth factors. Depending on their role in the immune response, cytokines can be categorized as pro-inflammatory or anti-inflammatory.

DAMPs: Damage-Associated Molecular Patterns are endogenous signals released from injured, stressed, or dying cells, such as extracellular ATP or uric acid crystals, that alert the immune system to tissue damage. These signals can activate the inflammasome, promoting inflammatory responses.  

Demyelination: a destructive process that causes damage to the myelin sheath that surrounds axons. In the central nervous system, the myelin sheath protects nerves in the brain, spinal cord and optic nerves. When this myelin sheath is damaged, the ability of the nerve to conduct electrical impulses slow or even stop.

Dopamine: a catecholamine neurotransmitter that plays key roles in the nervous system.

Dopaminergic Neurons: neurons that produce and release dopamine, a neurotransmitter involved in motor function, reward processing, behavior, and mood. These neurons are primarily produced in a region of the brain called substantia nigra.

Experimental Autoimmune Encephalomyelitis (EAE): a commonly used autoimmune-mediated model of multiple sclerosis (MS) induced by CD4+ T cells specific for myelin-derived antigens, and characterized by paralysis resulting from inflammation, demyelination, axonal injury, and neurodegeneration in the central nervous system (CNS).

Gasdermin: a family of pore-forming proteins that are the primary executioners of pyroptosis, a type of inflammatory cell death. Gasdermins have a two-domain structure, and upon cleavage by enzymes like caspases, an active N-terminal domain is released to form pores in the cell membrane.

Genetic Risk:  the likelihood that an individual carries a particular disease-associated mutation or is affected by a specific genetic disorder.

Immune-Mediated Inflammation: describes the condition where the inflammatory pathways of the immune system drive inflammation. Within the brain, immune-mediated inflammation includes cellular infiltration (T cells, B cells, and macrophages) as well as activation of proinflammatory cytokines. In MS, the immune-mediated inflammation targets myelin, contributing to lesion formation.

Inflammasome: a cytosolic multiprotein complex that assembles in response to pathogen-associated or damage-associated molecular patterns (PAMPs/DAMPs). It typically consists of a pattern recognition receptor (e.g. NLRP3), the adaptor protein ASC, and pro-caspase-1. Upon activation, it mediates caspase-1-dependent maturation of pro-inflammatory cytokines IL-1β and IL-18 and induces pyroptosis, contributing to innate immune defense and inflammatory pathology.

Lewy Bodies: large deposits of alpha-synuclein that accumulate within neurons. These clumps are hallmark of Parkinson’s disease.

Microglia: one of the neuroglial cell types present in the brain and spinal cord. Constituting approximately 10-15% of the total cellular population in the brain, microglial cells function as the primary immune cells of the central nervous system. These cells are essential for maintaining homeostasis, clearing cellular debris, and providing critical support functions within the brain.

Misfolded Proteins: proteins are composed of linear chains of amino acids that must fold into a functional three-dimensional structure. When these chains fail to fold properly, the resulting proteins can adopt abnormal shapes. These proteins are typically insoluble, and disrupt normal cellular processes. The accumulation of misfolded proteins is closely linked with several neurodegenerative diseases, including Alzheimer’s disease (AD), Parkinson’s disease (PD), Huntington’s disease (HD), and Amyotrophic Lateral Sclerosis (ALS).

Multiple Sclerosis (MS): the most commonly demyelinating disease of the central nervous system (CNS); MS is an immune-mediated disease, involving T cell, B cells, microglia, and macrophages, and characterized by inflammation, demyelination, axonal injury, and neurodegeneration.

Neurodegeneration: a complex, multifactorial process resulting in the loss of neurons.

Neurofibrillary Tangles: abnormal accumulations of tau inside neurons. In healthy neurons, tau proteins help stabilize the structure of microtubules, in certain neurodegenerative conditions, such as Alzheimer's disease, tau proteins become hyperphosphorylated, causing them to clump together and form twisted, thread-like structures known as tangles. 

Neuroinflammation: an inflammatory response within the central nervous system (CNS), primarily involving the activation of microglia and astrocytes. This process can be triggered by various factors, including infections, traumatic brain injury, toxic metabolites, and autoimmune diseases.  

NLRP3 Inflammasome: a cytosolic multi-protein complex found primarily in neuroinflammatory cells like microglia and astrocytes, and peripheral immune cells. The NLRP3 inflammasome plays a key role in the immune response by activating caspase-1 in response to various stress signals or infections, leading to the release of proinflammatory cytokines like IL-1β and IL-18, as well as the pore-forming molecule GSDMD. This inflammatory process can contribute to chronic inflammation and neurodegeneration, making NLRP3 a potential target for therapeutic intervention in neurodegenerative diseases.

Oligodendrocyte: one of the neuroglial cell types present in the brain and spinal cord. Constituting approximately 20-40% of all glial cells, oligodendrocytes represent approximately 10-20% of all brain cells. Oligodendrocytes are the cells that produce and maintenance the myelin sheath. A single oligodendrocyte will extend its processes to multiple axons, and ensheathing multiple segments with the protective myelin layers.

PAMPs: Pathogen-Associated Molecular Patterns are components of microbes, such as LPS or viral RNA, that are detected by pattern recognition receptors. Their recognition can lead to activation of the inflammasome, a multiprotein complex that drives inflammation.

Parkinson's Disease (PD): a neurodegenerative disease that is characterized by: (a) movement-related (motor) symptoms, including resting tremor, bradykinesia, rigidity, and postural instability, related to the loss of dopaminergic neurons in the substantia nigra; and (b) non-motor symptoms including anxiety, depression, apathy, hallucinations, constipation, orthostatic hypotension, sleep disorders, hyposmia/anosmia, and cognitive impairment.

Protein Aggregates: clusters of misfolded proteins that clump together inside or around cells like tangled balls of yarn.

Pyroptosis: a pro-inflammatory form of programmed cell death characterized by gasdermin D-mediated cell membrane pore formation, resulting in cell swelling and osmotic lysis, resulting in rupture of the plasma membrane and the release of pro-inflammatory mediators. Pyroptosis plays a protective role in host defense but also contributes to the pathogenesis of various inflammatory, autoimmune, and neurodegenerative diseases when dysregulated.

Substantia Nigra: a dopaminergic nucleus in the midbrain which plays a critical role in modulating motor and reward functions as part of the basal ganglia circuitry.

Tau: a protein that plays a crucial role in maintaining the stability and function of neurons in the brain. It is predominantly found in neurons, where it stabilizes microtubules, which are part of the cell's cytoskeleton. Microtubules are essential for maintaining cell shape, enabling intracellular transport, and facilitating cellular division. Hyperphosphorylation of tau is evident in various neurodegenerative diseases, where the abnormally phosphorylated molecules lead to the detachment of tau from the microtubules. These detached tau proteins can aggregate to form insoluble fibrils, known as neurofibrillary tangles. Diseases impacted by tau aggregation are called tauopathies, and include Alzheimer's disease, progressive supranuclear palsy, frontotemporal dementia (FTD), and corticobasal degeneration.