K+ efflux is the Common Trigger of NLRP3 inflammasome Activation by Bacterial Toxins and Particulate Matter

By Raúl Muñoz-Planillo, Peter Kuffa, Giovanny J. Martínez-Colón, B. L. Smith, Thekkelnaycke M. Rajendiran, G. Núñez. Immunity, 2013

1,993 citations recorded by the source corpus.

Summary The NLRP3 inflammasome is an important component of the innate immune system. However, its mechanism of activation remains largely unknown. We show that NLRP3 activators including bacterial pore-forming toxins, nigericin, ATP and particulate matter caused mitochondrial perturbation or the opening of a large membrane pore; but this was not required for NLRP3 activation. Furthermore, reactive oxygen species generation or a change in cell volume was not necessary for NLRP3 activation. Instead, the only common activity induced by all NLRP3 agonists was the permeation of the cell membrane to K+ and Na+. Notably, reduction of the intracellular K+ concentration was sufficient to activate NLRP3 whereas an increase in intracellular Na+ modulated, but was not strictly required for inflammasome activation. These results provide a unifying model for the activation of the NLRP3 inflammasome in which a drop in cytosolic K+ is the common step that is necessary and sufficient for caspase-1 activation.

Subfields: Molecular Biology, Nephrology

View Paper: https://www.semanticscholar.org/paper/a093fda276b61ebb647817d3d7e1bba672041921

How researchers see this paper

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In Molecular Biology

1. T. Kanneganti
2. M. Lamkanfi
3. S. Man
4. G. Núñez
5. V. Dixit
6. Yuan He
7. H. Hara
8. D. Sharma

In Nephrology

1. T. Kanneganti
2. G. Núñez
3. E. Latz

Citations in the corpus

• Regulation of inflammasome activation (2015, background): “Instead, a common event induced by classical canonical NLRP3 activators is a reduction in intracellular potassium concentration, which is responsible for activating the NLRP3 inflammasome (53).”
• Redox Regulation of NLRP3 Inflammasomes: ROS as Trigger or Effector? (2015, background): “K + efflux was the first model described that linked all known NLRP3 activators at the time, including ATP, nigericin, MSU crystals, and pore-forming toxins (93,107).”
• Mechanisms and functions of inflammasomes. (2014, background): “, 2013) have important roles in the Nlrp3 pathway (Ermler et al., 2014; He et al., 2013; Masters et al., 2010; Muñoz-Planillo et al., 2013).”
• The P2X7 Receptor in Infection and Inflammation (2017, positive): “…has been implicated, but it is doubtful whether Ca2+ as well as Na+ influx have any role in this process, and thus the decrease of intracellular K+ is a major driver of P2X7R-dependent NLRP3 inflammasome activation but the molecular mechanism involved is unknown (Muñoz-Planillo et al., 2013).”
• The cell biology of inflammasomes: Mechanisms of inflammasome activation and regulation (2016, background): “…signals required for NLRP3 activation (Cruz et al., 2007; Pétrilli et al., 2007; Cassel et al., 2008; Dostert et al., 2008; Halle et al., 2008; Hornung et al., 2008; Schorn et al., 2011; Zhou et al., 2011; Compan et al., 2012; Lee et al., 2012; Murakami et al., 2012; Muñoz-Planillo et al., 2013).”