NLRP3 inflammasome in neurodegenerative disease

Neurodegenerative diseases are characterized by a dysregulated neuro-glial microenvironment, culminating in func-tional deficits resulting from neuronal cell death. Inflammation is a hallmark of the neurodegenerative microenviron-ment and despite a critical role in tissue homeostasis, increasing evidence suggests that chronic inflammatory insult can contribute to progressive neuronal loss. Inflammation has been studied in the context of neurodegenerative disor-ders for decades but few anti-inflammatory treatments have advanced to clinical use. This is likely due to the related challenges of predicting and mitigating off-target effects impacting the normal immune response while detecting inflammatory signatures that are specific to the progression of neurological disorders. Inflammasomes are pro -inflam-matory cytosolic pattern recognition receptors functioning in the innate immune system. Compelling pre-clinical data has prompted an intense interest in the role of the NLR family pyrin domain containing 3 (NLRP3) inflammasome in neurodegenerative disease. NLRP3 is typically inactive but can respond to sterile triggers commonly associated with neurodegenerative disorders including protein misfolding and aggregation, mitochondrial and oxidative stress, and exposure to disease-associated environmental toxicants. Clear evidence of enhanced NLRP3 inflammasome activity in common neurodegenerative diseases has coincided with rapid advancement of novel small molecule therapeutics making the NLRP3 inflammasome an attractive target for near-term interventional studies. In this review, we highlight evidence from model systems and patients indicating inflammasome activity in neurodegenerative disease associated with the NLRP3 inflammasome's ability to recognize pathologic forms of amyloid-fl, tau, and alpha-synuclein. We discuss inflammasome-driven pyroptotic processes highlighting the potential utility of evaluating extracellular inflamma-some-related proteins in the context of biomarker discovery. We complete the report by pointing out gaps in our understanding of intracellular modifiers of inflammasome activity and mechanisms regulating the resolution of inflammasome activation. The literature review and perspectives provide a conceptual platform for continued analysis of inflammation in neurodegenerative diseases through the study of inflammasomes and pyroptosis, mechanisms of inflammation and cell death now recognized to function in multiple highly prevalent neurological disorders.

Automated summary

Neurodegenerative diseases are characterized by dysregulated neuro-glial microenvironment and chronic inflammation, which can lead to progressive neuronal loss. The NLRP3 inflammasome has gained interest as a potential target for anti-inflammatory treatments due to its involvement in recognizing pathologic forms of amyloid, tau, and alpha-synuclein. However, there are still gaps in our understanding of how intracellular modifiers and resolution mechanisms regulate inflammasome activation. Further analysis of inflammasome-driven pyroptosis and inflammation in neurodegenerative diseases is important for developing effective therapeutics and biomarkers.