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Fig. 2 | Particle and Fibre Toxicology

Fig. 2

From: The complex cascade of cellular events governing inflammasome activation and IL-1β processing in response to inhaled particles

Fig. 2

Cellular signals responsible for particle-induced inflammasome activation. Inflammasome activation after particle exposure results from various intracellular events (called signal 2) that are non-mutually exclusive. When endocytosed, nano- and micrometric-particles or exogenous NLRP3 complexes induce lysosomal destabilization and interfere with autophagy/mitophagy resulting in the release of ROS (Reactive oxygen species), cathepsins (Cat) or calcium in the cytosol. These vesicular leaking molecules promote the assembly of inflammasome components (NLRP3/ASC/Caspase-1) and subsequent IL-1β maturation from inactive pro-IL-1β form. Oxidative stress and active cathepsins modify undetermined protein structures which are recognized by the NLRP3 inflammasome. High calcium concentrations due to lysosomal but also endoplasmic reticulum release or extracellular influx via TRP (Transient receptor potential) calcium-channels affect mitochondria which release high amount of ROS. TAK1 (Tat-associated kinase), a kinase activated by increased intracellular calcium, is also implicated in inflammasome processing. Depletion in intracellular potassium is mandatory for inflammasome activation. Potassium cell efflux is indeed a necessary and sufficient signal for inflammasome activation and IL-1β processing. ATP release upon cell membrane damage permeates P2X7R (P2X purinoceptor 7) channels to potassium. Particle endocytosis is not systematically required and contact between cell membrane and particles resulting in the formation of lipid rafts is sufficient to trigger inflammasome engagement through SYK (Spleen tyrosine kinase) activation. The small size of nanoparticles allows them to cross biological membranes. Nanoparticles reach the cytosol even in absence of active endocytic process and may damage organelles such as mitochondria. Water movements through AQP (Aquaporin) 1 are necessary for inflammasome activation. Water channels are involved in inflammasome by regulating cytoskeleton rearrangement, ionic movements and TRP activation

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