Journal of Molecular Biology
ReviewThe NLRP3 Inflammasome Renders Cell Death Pro-inflammatory
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Section snippets
Historical background on NLRP3 activation and the K+ efflux theory
NLRP3 is the most studied inflammasome sensor due to its crucial involvement in both infection-triggered and sterile inflammation [16]. Although the exact molecular mechanism of its activation remains unknown, NLRP3 is appreciated as a sensor of membrane and cellular integrity. Under steady-state conditions, membrane integrity ensures a chemical disequilibrium of cations with high intracellular K+ on the one hand and high extracellular Na+ concentrations on the other hand. When perturbations of
NLRP3 activation in the context of programmed cell death
Bacterial pore-forming toxins, ionophores, and ATP that directly trigger potassium efflux have proven to be vital tools for the characterization of NLRP3 biology in vitro, yet the overall relevance of these triggers in disease pathology in vivo remains mostly limited to the ATP–P2X7 axis [28]. Instead, the surveillance of cell viability by NLRP3 by monitoring the intracellular potassium concentration is more likely to be the core and broadly applicable function of NLRP3 in vivo. To this effect,
Exceptions to the rule: K+ efflux-independent activation of NLRP3
Although the majority of known NLRP3 agonists activate the inflammasome pathway by triggering potassium efflux, there have been scarce reports on potassium efflux-independent NLRP3 activation. Those can be broadly categorized into two groups: First, there are NLRP3 agonists that endanger cellular integrity, for example, high osmotic pressure [71] or blockade of glycolysis [72] and oxidative phosphorylation [73]. With potassium efflux being dispensable, ROS production was again proposed as the
Final remarks
Almost 30 years after the first descriptions that pore-forming toxins could trigger IL-1β secretion from LPS-stimulated monocytes, accumulating evidence on the NLRP3 inflammasome outlines a sensing modality that functions to monitor perturbations to cellular integrity. For all we know, the main pathway of how NLRP3 senses cellular perturbations relies on monitoring of intracellular potassium levels. This enables NLRP3 to be activated not only directly by potassium efflux inducing agents but also
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2022, Biomedicine and PharmacotherapyCitation Excerpt :Correspondingly, NALP3 inflammasome activation is triggered by eATP via P2X7-ASC axis, resulting in enhanced anti-tumor immunity responses in mouse model, which are supported by increased active IL-1β and IL18 release [9]. Another study has uncovered the critical importance of active P2X7 triggered by liberated eATP, which then stimulates the NLRP3 inflammasome and processes pro-IL-1β and pro-IL-18 to their mature, active forms [27]. However, additional mechanism has been described to regulate eATP levels in the TME involving higher level of CD39 in various human tumors than normal tissues (Fig. 2) [28–30], and thus favoring eATP hydrolysis to eADO.