What is an Inflammasome?

An inflammasome is a cytosolic multiprotein complex that assembles in response to harmful stimuli such as pathogen-associated molecular patterns (PAMPs) or damage-associated molecular patterns (DAMPs). It typically includes a sensor protein (e.g. NLRP3), the adaptor ASC, and pro-caspase-1. Upon activation, the inflammasome facilitates the cleavage of pro-inflammatory cytokines IL-1β and IL-18 and induces pyroptosis, a form of inflammatory cell death.

Inflammasome activation generally involves two-steps:

• Priming: The priming step is often mediated by NF-κB signaling, which increases the transcription of inflammasome components such as NLRP3, pro-IL-1β and pro-IL-18.
• Activation: A second signal – such as ATP release, ion flux, lysosomal rupture, or mitochondrial stress – triggers assembly of the inflammasome complex and activation of caspase-1, leading to cytokine maturation and pyroptosis (Guo, 2015).

Yes. Inflammasomes, particularly NLRP3, are promising therapeutic targets in diseases characterized by chronic inflammation. Inhibiting inflammasome components such as NLRP3, caspase-1, or IL-1β has demonstrated efficacy in both preclinical and clinical studies.

Aberrant or prolonged inflammasome activation has been linked to a wide range of diseases, including:

• Metabolic disorders: Gout, type 2 diabetes, obesity
• Cardiovascular diseases: Atherosclerosis, heart failure
• Autoimmune and autoinflammatory conditions: Rheumatoid arthritis, systemic lupus erythematosus (SLE), familial cold autoinflammatory syndrome (FCAS)
• Neurodegenerative diseases: Alzheimer’s disease (AD), Parkinson’s disease (PD), amyotrophic lateral sclerosis (ALS), multiple sclerosis (MS)
• Cancer: Colorectal, liver and gastric cancers

Pyroptosis is a pro-inflammatory form of programmed cell death characterized by cell membrane pore formation, cell swelling, and rupture (Yu, 2021). It is mediated by gasdermin D, which is cleaved by inflammatory caspases such as caspase-1. This process facilitates the release of pro-inflammatory cytokines, contributing to host defense. However, dysregulated pyroptosis has been implicated in the pathogenesis of various inflammatory and autoimmune diseases.

ASC (apoptosis-associated speck-like protein containing a CARD) is an adaptor protein essential for canonical inflammasome signaling. It contains both a pyrin domain (PYD) and a caspase activation and recruitment domain (CARD), allowing it to mediate the interaction between pattern recognition receptors (PRRs, e.g. NLRP3) and pro-caspase-1.

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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.  

Amyotrophic Lateral Sclerosis (ALS): also known as Lou Gehrig's disease, it is the most common form of motor neuron disease and affects the upper and lower motor neurons. This fatal neuromuscular disease is characterized by progressive weakness of the muscles required to move, speak, eat, and breathe. 

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.

Cytokine: a protein that serves as a signaling molecule among immune system cells. Cytokines are classified into interleukins, interferons, tumor 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.   

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.

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.  

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. 

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.  

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.