Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
Review
. 2020 Jun 23;21(12):4459.
doi: 10.3390/ijms21124459.

Multifactorial Activation of NLRP3 Inflammasome: Relevance for a Precision Approach to Atherosclerotic Cardiovascular Risk and Disease

Affiliations
Review

Multifactorial Activation of NLRP3 Inflammasome: Relevance for a Precision Approach to Atherosclerotic Cardiovascular Risk and Disease

Andrea Baragetti et al. Int J Mol Sci. .

Abstract

Chronic low-grade inflammation, through the specific activation of the NACHT leucine-rich repeat- and PYD-containing (NLRP)3 inflammasome-interleukin (IL)-1β pathway, is an important contributor to the development of atherosclerotic cardiovascular disease (ASCVD), being triggered by intracellular cholesterol accumulation within cells. Within this pathological context, this complex pathway is activated by a number of factors, such as unhealthy nutrition, altered gut and oral microbiota, and elevated cholesterol itself. Moreover, evidence from autoinflammatory diseases, like psoriasis and others, which are also associated with higher cardiovascular disease (CVD) risk, suggests that variants of NLRP3 pathway-related genes (like NLRP3 itself, caspase recruitment domain-containing protein (CARD)8, caspase-1 and IL-1β) may carry gain-of-function mutations leading, in some individuals, to a constitutive pro-inflammatory pattern. Indeed, some reports have recently associated the presence of specific single nucleotide polymorphisms (SNPs) on such genes with greater ASCVD prevalence. Based on these observations, a potential effective strategy in this context may be the identification of carriers of these NLRP3-related SNPs, to generate a genomic score, potentially useful for a better CVD risk prediction, and, possibly, for personalized therapeutic approaches targeted to the NLRP3-IL-1β pathway.

Keywords: NLRP3 inflammasome; atherosclerosis; cardiovascular disease; interleukin-1β; low-grade inflammation; single nucleotide polymorphism.

PubMed Disclaimer

Conflict of interest statement

A.B.: no conflict of interest. A.L.C. has received honoraria, lecture fees, or research grants from: Akcea, Amgen, Astrazeneca, Eli Lilly, Genzyme, Kowa, Mediolanum, Menarini, Merck, Pfizer, Recordati, Sanofi, Sigma Tau, Medco, Amryt. P.M.: has received honoraria, lecture fees, or research grants from: Montefarmaco OTC, Bayer.

Figures

Figure 1
Figure 1
Summary of cellular mechanisms leading to the activation of the NLRP3 inflammasome. Depending on the pathogenic activator, two different types of cellular mechanisms lead to the assembly and activation of NLRP3 inflammasome, crucial for the production of atherogenic molecules (interleukin (IL)-1β). (A) The “canonical pathway” is (1) activated by the phagocytosis of molecular products (e.g., cholesterol crystals in the atherosclerotic lesion) or peculiar pathogen-associated molecules or cellular stimuli (e.g., ATP via the P2X7 receptor), and involves (2) the activation of lysosomial cathepsins and (3) pro-apoptotic mitochondrial signals. (B) The “non-canonical pathway” evolutionary developed for the phagocytosis of peculiar bacterial species, (1) either by endocytosis or by direct invasion; this in turn (2) activates programmed digestion of these products with the release of virulent proteins from the wall membrane of bacteria which (3) induce the assembly of caspase 11. Both mechanisms induce massive efflux of potassium, which is then crucial for the assembly of the components of the NLRP3 inflammasome. This will finally turn pro-caspase 1 into active caspase 1 to favor the release of the final mature form of IL-1β. mtDNA, mitochondrial DNA; ROS, reactive oxygen species; CARD, caspase activation and recruitment domain.
Figure 2
Figure 2
Different agents trigger (after a priming process) the activation of the NLRP3 inflammasome-IL-1β pathway to promote atherosclerosis. ASC, apoptosis-associated speck-like protein containing a caspase recruitment; ATP, adenosine triphosphate; CARD, caspase recruitment domain–containing protein; IL-1β, interleukin IL-1β; IL-6, interleukin 6; LRR, leucine-rich repeats; ROS, reactive oxygen radicals; TLR, Toll-like receptor.

Similar articles

Cited by

References

    1. Libby P., Hansson G.K. From Focal Lipid Storage to Systemic Inflammation: JACC Review Topic of the Week. J. Am. Coll. Cardiol. 2019;74:1594–1607. doi: 10.1016/j.jacc.2019.07.061. - DOI - PMC - PubMed
    1. Zhang W., Song M., Qu J., Liu G.H. Epigenetic Modifications in Cardiovascular Aging and Diseases. Circ. Res. 2018;123:773–786. doi: 10.1161/CIRCRESAHA.118.312497. - DOI - PubMed
    1. Ference B.A., Ginsberg H.N., Graham I., Ray K.K., Packard C.J., Bruckert E., Hegele R.A., Krauss R.M., Raal F.J., Schunkert H., et al. Low-density lipoproteins cause atherosclerotic cardiovascular disease. 1. Evidence from genetic, epidemiologic, and clinical studies. A consensus statement from the European Atherosclerosis Society Consensus Panel. Eur. Heart J. 2017;38:2459–2472. doi: 10.1093/eurheartj/ehx144. - DOI - PMC - PubMed
    1. Mach F., Baigent C., Catapano A.L., Koskinas K.C., Casula M., Badimon L., Chapman M.J., De Backer G.G., Delgado V., Ference B.A., et al. 2019 ESC/EAS Guidelines for the management of dyslipidaemias: Lipid modification to reduce cardiovascular risk. Eur. Heart J. 2019;290:140–205. doi: 10.1016/j.atherosclerosis.2019.08.014. - DOI - PubMed
    1. Ahlin G., Hilgendorf C., Karlsson J., Szigyarto C.A., Uhlén M., Artursson P. Endogenous gene and protein expression of drug-transporting proteins in cell lines routinely used in drug discovery programs. Drug Metab. Dispos. 2009;37:2275–2283. doi: 10.1124/dmd.109.028654. - DOI - PubMed

MeSH terms

Substances