NLRP3 Inflammasome Activation in Diabetic Complications
Summary
Chronic hyperglycaemia in diabetes precipitates a sterile inflammatory cascade central to the pathogenesis of multiple end-organ complications. At the heart of this cascade lies the NLRP3 inflammasome, a cytosolic multiprotein sensor that detects metabolic stress signals—such as mitochondrial reactive oxygen species, ionic imbalances and thioredoxin-interacting protein accumulation—and activates caspase-1. Caspase-1, in turn, processes the pro-inflammatory cytokines interleukin-1β and interleukin-18, and cleaves gasdermin D to trigger pyroptotic cell death. Persistent activation of NLRP3-mediated pyroptosis contributes to the structural and functional disruption of cardiac myocytes, endothelial cells and renal epithelial cells, underpinning diabetic cardiomyopathy, nephropathy and neuropathy. Recent mechanistic insights have linked NLRP3 activity to diverse pathways including NF-κB-dependent transcriptional priming, P2X7 receptor-mediated ionic flux and dysregulation of autophagy. This emergent knowledge underscores NLRP3 as both a biomarker of tissue injury and a promising target for therapies aimed at curbing inflammation and preserving organ function in diabetes.
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NLRP3 Inflammasome Activation in Diabetic Complications publication trend
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Technical terms
Pyroptosis: A lytic form of programmed cell death driven by inflammasome-activated caspases and gasdermin pore formation, resulting in release of inflammatory mediators.
NLRP3 inflammasome: A multiprotein innate immune complex that senses cellular stress and activates caspase-1, leading to cytokine maturation and pyroptosis.
P2X7 receptor: A purinergic ligand-gated ion channel that facilitates NLRP3 activation through ATP-mediated ion flux and reactive oxygen species generation.
Gasdermin D: A pore-forming effector protein cleaved by active caspase-1, essential for membrane permeabilisation during pyroptosis.
Thioredoxin-interacting protein (TXNIP): An oxidative stress sensor that binds to NLRP3, promoting inflammasome assembly and activation.
References
- Puerarin Inhibits NLRP3-Caspase-1-GSDMD-Mediated Pyroptosis via P2X7 Receptor in Cardiomyocytes and Macrophages. International Journal of Molecular Sciences (2023).
- Role of pyroptosis in diabetic cardiomyopathy: an updated review. Frontiers in Endocrinology (2024).
- BMP-7 Attenuates Inflammation-Induced Pyroptosis and Improves Cardiac Repair in Diabetic Cardiomyopathy. Cells (2021).
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