NLRP3 Inflammasome

The NLRP3 inflammasome is a cytoplasmic supramolecular complex that is activated in response to cellular perturbations triggered by infection and sterile injury. ^[1] Inflammasomes are multi-protein signaling complexes that trigger the activation of inflammatory caspases and the maturation of interleukin-1β, and among them the NLRP3 inflammasome is best characterized and has been linked with various human autoinflammatory and autoimmune diseases. ^[2]

Assembly of the NLRP3 inflammasome leads to activation of caspase-1, which induces the maturation and release of interleukin-1β (IL-1β) and IL-18, as well as cleavage of gasdermin D (GSDMD), which promotes a lytic form of cell death. ^[1] As a central instigator of the inflammatory response to infection and tissue damage, NLRP3 assembles a cytosolic innate immune complex that activates caspase-1, which in turn cleaves gasdermin D to induce pyroptosis, a highly inflammatory regulated mode of lytic cell death. ^[3] Danger signals activate the cytosolic innate immune receptor NLRP3, which once activated nucleates assembly of an inflammasome, leading to caspase-1-mediated proteolytic activation of the IL-1β family of cytokines and an inflammatory, pyroptotic cell death. ^[4]

NLRP3 inflammasome activation is among the potential mechanisms of inflammageing, the condition of elevated blood inflammatory markers that most older individuals develop and that carries high susceptibility to chronic morbidity, disability, frailty, and premature death. ^[5] Pathological activation of the NLRP3 inflammasome-IL-1β pathway by metabolic stress, ageing and the microbiome is observed in obesity and contributes to the development of type 2 diabetes and its complications. ^[6] Production of IL-1β via NLRP3 can contribute to the pathogenesis of inflammatory disease, whereas aberrant IL-1β secretion through inherited NLRP3 mutations causes autoinflammatory disorders. ^[1]

The NLRP3 inflammasome has emerged as a key regulator in diverse rheumatic, metabolic and neurodegenerative diseases, and small-molecule and biologic inhibitors are advancing into the clinic to harness the therapeutic potential of modulating it. ^[3] Pharmacological inhibition of NLRP3 activation results in potent therapeutic effects in a wide variety of rodent models of inflammatory diseases, effects that are mirrored by genetic ablation of NLRP3. ^[4] In metabolic disease, the glucose-lowering effects of IL-1 antagonism highlight the prospect of targeting the NLRP3 inflammasome-IL-1β pathway for the treatment of type 2 diabetes and its comorbidities, though the safety of NLRP3 inhibition remains under evaluation. ^[6]