Molecular Structure and Assembly

• The NLRP3 inflammasome consists of three parts: NLRP6 detection protein, ASC adapter protein, and pro-caspase 1 compound.
• Structure: Nucleotide-binding and oligomerization domain (NACHT), C-terminal leucine-rich repeat domain (LRR), and N-terminal pyrin domain (PYD).
• Senses stressors and triggers inflammatory reactions.

Activation Mechanisms and Signalling Pathways

• Requires two signals: Priming (NF-κB-mediated upregulation) and Activation (various stimuli).
• Activation stimuli: Potassium efflux, Calcium signalling perturbations, Mitochondrial dysfunction, Lysosomal damage, Reactive oxygen species (ROS).
• Leads to ASC recruitment, pro-caspase-1 activation, and processing of IL-1β and IL-18 cytokines.

Physiological Functions and Regulation

• Functions: Recognition of stress and damage, Initiation of inflammatory responses, Coordination of innate immune responses, Regulation of cell death pathways.
• Regulatory mechanisms: Ubiquitination and de-ubiquitination, Phosphorylation, microRNA-mediated regulation, Autophagy-dependent control, Metabolic regulation.

Role in Disease Pathogenesis

• Dysregulation implicated in diseases:
• Inflammatory Diseases: Gout, Atherosclerosis, Type 2 diabetes, Obesity-related inflammation, Inflammatory bowel disease.
• Neurodegenerative Disorders: Alzheimer's, Parkinson's, Multiple sclerosis, Amyotrophic lateral sclerosis.
• Other Conditions: COVID-19, Cancer, Cardiovascular diseases, Metabolic disorders, Autoimmune conditions.

Therapeutic Approaches and Future Perspectives

• Current strategies: Direct NLRP3 inhibition (Small molecule inhibitors, Compounds blocking ASC oligomerization, Peptide-based inhibitors), Indirect modulation (Targeting upstream activators, Enhancing negative regulators, Modifying cellular metabolism, Anti-inflammatory compounds).
• Ongoing research:
• Creating inhibitors targeting NLRP3 receptor protein in tissues.
• Exploring effectiveness of combined treatment approaches.
• Biomarkers for personalized medicine.
• Understanding significance of NLRP3 in diseases.
• Elucidating tissue-specific functions.
• Developing more selective therapeutic agents.
• Understanding interplay with other inflammatory pathways.
• Investigating role in aging and longevity.