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NLRP3 Inflammasome in Cardiovascular Disease: David's Stone against Goliath?

Serban Balanescu
Serban Balanescu
, 
Elena Barbu
Elena Barbu
, 
Camelia Georgescu
Camelia Georgescu
 e 
Andreea Catarina Popescu
Andreea Catarina Popescu
   | 05 mag 2022
Romanian Journal of Cardiology's Cover Image
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Article Category: Review
Pubblicato online: 05 mag 2022
Pagine: 517 - 527
DOI: https://doi.org/10.47803/rjc.2021.31.3.517
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© 2021 Serban Balanescu et al., published by Sciendo
This work is licensed under the Creative Commons Attribution 4.0 International License.

Figure 1

The molecular structure of the inflammasome. This is a large complex multimeric protein consisting of oligomerized NLRP. This consists of a central NOD immune receptor, a leucine-rich repeat (LRR) domain acting like an activation sensor and an effector domain, either a pyrin-containing (PYD) or a caspase activation and recruiting domain – CARD. When activated, the effector domain of NLRP interacts with an adaptor protein (ASC) via a CARD molecule and activate pro-caspase1 into mature caspase1. Pro-caspase1 also has a CARD molecule allowing interaction with the inflammasome.
The molecular structure of the inflammasome. This is a large complex multimeric protein consisting of oligomerized NLRP. This consists of a central NOD immune receptor, a leucine-rich repeat (LRR) domain acting like an activation sensor and an effector domain, either a pyrin-containing (PYD) or a caspase activation and recruiting domain – CARD. When activated, the effector domain of NLRP interacts with an adaptor protein (ASC) via a CARD molecule and activate pro-caspase1 into mature caspase1. Pro-caspase1 also has a CARD molecule allowing interaction with the inflammasome.

Figure 2

The two main steps for full inflammasome activation. Initiation of the process is priming which leads to increased expression of NLRP3 and pro-IL-1b via nuclear factor-kappa B. This acts as a second messenger for toll-like receptor activation via DAMPs or PAMPs; an alternative pathway is NF-kB stimulation by TNF receptor and TNFa. Triggering or full activation of the inflammasome is the final oligomerization of NLRP3 with procaspase-1 cleaving properties. It can be induced by intracellular signaling due to increased ROS generation by dysfunctional mitochondria, potassium efflux or calcium influx, or lysosomal lysis after LDL crystal endocytosis.
The two main steps for full inflammasome activation. Initiation of the process is priming which leads to increased expression of NLRP3 and pro-IL-1b via nuclear factor-kappa B. This acts as a second messenger for toll-like receptor activation via DAMPs or PAMPs; an alternative pathway is NF-kB stimulation by TNF receptor and TNFa. Triggering or full activation of the inflammasome is the final oligomerization of NLRP3 with procaspase-1 cleaving properties. It can be induced by intracellular signaling due to increased ROS generation by dysfunctional mitochondria, potassium efflux or calcium influx, or lysosomal lysis after LDL crystal endocytosis.

Figure 3

Initiating factors and activation pathways of inflammasomes and consecutive inflammation. Either PAMPs or DAMPs act on pattern recognition receptors, inflammasomes included. NLRP3 caspase-1 activation leads to IL-1b and IL-18 production and triggers the inflammatory response. CARD – caspase recruitment domain (NLRC4); TNF – Tumor Necrosis Factor; Th – T helper lymphocytes; Treg – T regulatory (suppressor) lymphocytes.
Initiating factors and activation pathways of inflammasomes and consecutive inflammation. Either PAMPs or DAMPs act on pattern recognition receptors, inflammasomes included. NLRP3 caspase-1 activation leads to IL-1b and IL-18 production and triggers the inflammatory response. CARD – caspase recruitment domain (NLRC4); TNF – Tumor Necrosis Factor; Th – T helper lymphocytes; Treg – T regulatory (suppressor) lymphocytes.

Figure 4

The systemic effects of NLRP3 caspase-1 mediated interleukin activation. Interleukin-6 generated by the potent stimulus of IL-1b leads to secretion of acute phase proteins in the liver, induces endothelial dysfunction and activates smooth muscle cells in arterial media. IL – interleukin; oxLDL – oxidated LDL molecule; CRP – C-reactive protein; PAI-1 – plasminogen activator inhibitor-1. (Adapted from (24).
The systemic effects of NLRP3 caspase-1 mediated interleukin activation. Interleukin-6 generated by the potent stimulus of IL-1b leads to secretion of acute phase proteins in the liver, induces endothelial dysfunction and activates smooth muscle cells in arterial media. IL – interleukin; oxLDL – oxidated LDL molecule; CRP – C-reactive protein; PAI-1 – plasminogen activator inhibitor-1. (Adapted from (24).

Overview of NLRP3 inhibitors, either specific or as „pleiotropic effects” of other therapeutic agents

Drug Main therapeutic effect NLRP3 inhibition
Atorvastatin LDL reduction by hepatocyte HMG-CoA inhibition Reduction of NLRP3 expression in mononuclear cells; lowers IL-1b, IL-18
Colchicine Tubulin disruption with down-regulation of inflammatory pathways Prevents activation of NLRP3 by inhibiting oligomerization depending on cytoplasmic microtubules; inhibits caspase-1 gene transcription
Canakinumab Monoclonal-antibody against IL-1b Downregulates NLRP3 and IL-1 gene expression
Anakinra Recombinant IL-1b receptor antagonist Downstream inhibition of activated NLRP3 cascade
MCC950 Small molecule inhibitor of NLRP3 Specific for NLRP3; no effect on other inflammasomes
CY-09 Small molecule inhibitor of NLRP3 Specific for NLRP3, binds to the NOD (NACHT) immune receptor
Flavonoids Inhibit expression of NLRP3 and ASC; blocks inflammasome assembly Idem
PEDF Inhibits mitochondrial division Mitochondrial stabilization; reduces ROS production; promotes mitophagy in hypoxic cardiomyocytes
Tranilast Anthranilic acid anti-allergic, anti-asthmatic drug Binds to the NOD (NACHT) domain, to block NLRP3 oligomerization
Parthenolide Natural (sesquiterpene lactone) anti-inflammatory agent, COX inhibitor Blocks NLRP3 ATP-ase capacity and inactivates caspase-1
Oridonin Anti-neoplastic drug, inhibits angiogenesis and induces apoptosis Blocks NLRP3 activation by selective binding to cysteine
Pralnacasan (VX-740), Belnacasan (VX-765) Caspase-1 inhibitors Specific downstream inhibition of NLRP3 activation by caspase-1 blockage
Cilostazol Phosphodiesterase-3 inhibitor Reduces NLRP3 activation

Available proof for inflammatory pathways NLRP3-mediated in different conditions 8

Experimental In humans “in vivo”
Obesity Involved in pathogenesis of metabolic syndrome sdr Crohn's disease NLRP3 gene mutations involved in pathogenesis
Diabetes mellitus Acts as a sensor for metabolic imbalance, inducing DM Asthma, COPD Found activated in bronchial tree, leads to clinically relevant disease
Gout Activated by urate crystals deposition in synovium Neurodegenerative disorders Involved in pathogenesis of Alzheimer disease; chronic neuro-inflammation
Rheumatoid arthritis Downregulation protects against synovial damage Cancer NLRP3 involved in treatment-resistant leukemia. Activated in bronchogenic carcinoma (non-small cell type).
Haemorrhagic stroke NLRP3 inhibition reduces brain damage Cryopyrin-associated periodic syndromes* Main pathogenic mechanism
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