Journal of Molecular Biology
Volume 430, Issue 2, 19 January 2018, Pages 133-141
Journal home page for Journal of Molecular Biology

Review
The NLRP3 Inflammasome Renders Cell Death Pro-inflammatory

https://doi.org/10.1016/j.jmb.2017.11.013Get rights and content

Highlights

  • NLRP3 is activated by low intracellular potassium levels.

  • This pathway serves as a surveillance mechanism of plasma membrane integrity.

  • Due to this functionality, major forms of programmed cell death result in secondary NLRP3 activation.

Abstract

NLRP3 is the most studied inflammasome sensor due to its crucial involvement in sterile and infection-triggered inflammation. Although its molecular mode of activation remains to be defined, it is well established that low intracellular potassium concentrations result in its activation. This functionality allows the classical NLRP3 pathway to serve as a highly sensitive, but non-specific surveillance mechanism responding to any type of perturbation that breaches plasma membrane integrity and the associated potassium gradient across the membrane. Here, we review our current knowledge on potassium efflux-dependent NLRP3 activation, with a special focus on how major cell death programs are rendered pro-inflammatory by secondary NLRP3 activation. Apart from the “alternative inflammasome” as the major exception to the rule, this connection explains the fundamental importance of NLRP3 in cell death-associated inflammation and firmly establishes NLRP3 as a principal surveillance mechanism of cellular integrity.

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

References (75)

  • T.B. Kang et al.

    Caspase-8 blocks kinase RIPK3-mediated activation of the NLRP3 inflammasome

    Immunity

    (2013)
  • M. Yabal et al.

    XIAP restricts TNF- and RIP3-dependent cell death and inflammasome activation

    Cell Rep.

    (2014)
  • K.E. Lawlor et al.

    XIAP loss triggers RIPK3- and caspase-8-driven IL-1beta activation and cell death as a consequence of TLR-MyD88-induced cIAP1-TRAF2 degradation

    Cell Rep.

    (2017)
  • J.E. Vince et al.

    Inhibitor of apoptosis proteins limit RIP3 kinase-dependent interleukin-1 activation

    Immunity

    (2012)
  • M.M. Gaidt et al.

    Human monocytes engage an alternative Inflammasome pathway

    Immunity

    (2016)
  • S.S. Iyer et al.

    Mitochondrial cardiolipin is required for Nlrp3 inflammasome activation

    Immunity

    (2013)
  • K. Shimada et al.

    Oxidized mitochondrial DNA activates the NLRP3 inflammasome during apoptosis

    Immunity

    (2012)
  • A.J. Wolf et al.

    Hexokinase is an innate immune receptor for the detection of bacterial peptidoglycan

    Cell

    (2016)
  • M.M. Gaidt et al.

    Alternative inflammasome activation enables IL-1beta release from living cells

    Curr. Opin. Immunol.

    (2017)
  • C.A. Janeway

    Approaching the asymptote? Evolution and revolution in immunology

    Cold Spring Harb. Symp. Quant. Biol.

    (1989)
  • S.Y. Seong et al.

    Hydrophobicity: an ancient damage-associated molecular pattern that initiates innate immune responses

    Nat. Rev. Immunol.

    (2004)
  • P. Broz et al.

    Inflammasomes: mechanism of assembly, regulation and signalling

    Nat. Rev. Immunol.

    (2016)
  • V. Hornung et al.

    AIM2 recognizes cytosolic dsDNA and forms a caspase-1-activating inflammasome with ASC

    Nature

    (2009)
  • T. Fernandes-Alnemri et al.

    AIM2 activates the inflammasome and cell death in response to cytoplasmic DNA

    Nature

    (2009)
  • L. Franchi et al.

    Cytosolic flagellin requires Ipaf for activation of caspase-1 and interleukin 1beta in salmonella-infected macrophages

    Nat. Immunol.

    (2006)
  • E.M. Kofoed et al.

    Innate immune recognition of bacterial ligands by NAIPs determines inflammasome specificity

    Nature

    (2011)
  • E.D. Boyden et al.

    Nalp1b controls mouse macrophage susceptibility to anthrax lethal toxin

    Nat. Genet.

    (2006)
  • J. Chavarria-Smith et al.

    Direct proteolytic cleavage of NLRP1B is necessary and sufficient for inflammasome activation by anthrax lethal factor

    PLoS Pathog.

    (2013)
  • H. Xu et al.

    Innate immune sensing of bacterial modifications of Rho GTPases by the Pyrin inflammasome

    Nature

    (2014)
  • V. Petrilli et al.

    Activation of the NALP3 inflammasome is triggered by low intracellular potassium concentration

    Cell Death Differ.

    (2007)
  • H. Cui et al.

    Effector-triggered immunity: from pathogen perception to robust defense

    Annu. Rev. Plant Biol.

    (2015)
  • L.M. Stuart et al.

    Effector-triggered versus pattern-triggered immunity: how animals sense pathogens

    Nat. Rev. Immunol.

    (2013)
  • S. Bhakdi et al.

    Release of interleukin-1 beta associated with potent cytocidal action of staphylococcal alpha-toxin on human monocytes

    Infect. Immun.

    (1989)
  • D. Perregaux et al.

    IL-1 beta maturation: evidence that mature cytokine formation can be induced specifically by nigericin

    J. Immunol.

    (1992)
  • I. Walev et al.

    Potassium-inhibited processing of IL-1 beta in human monocytes

    EMBO J.

    (1995)
  • M.A. Katsnelson et al.

    K+ efflux agonists induce NLRP3 inflammasome activation independently of Ca2 + signaling

    J. Immunol.

    (2015)
  • M.J. Daniels et al.

    Fenamate NSAIDs inhibit the NLRP3 inflammasome and protect against Alzheimer's disease in rodent models

    Nat. Commun.

    (2016)
  • Cited by (82)

    • CD39 – A bright target for cancer immunotherapy

      2022, Biomedicine and Pharmacotherapy
      Citation 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.

    View all citing articles on Scopus
    View full text