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
. 2023 Jan 25;11(2):261.
doi: 10.3390/vaccines11020261.

Neutrophil Extracellular Traps and NLRP3 Inflammasome: A Disturbing Duo in Atherosclerosis, Inflammation and Atherothrombosis

Puneetpal Singh  1 , Nitin Kumar  1 , Monica Singh  1 , Manminder Kaur  2 , Gurjinderpal Singh  3 , Amit Narang  4 , Abhinav Kanwal  5 , Kirti Sharma  1 , Baani Singh  1 , Mario Di Napoli  6 , Sarabjit Mastana  7
Affiliations
Review

Neutrophil Extracellular Traps and NLRP3 Inflammasome: A Disturbing Duo in Atherosclerosis, Inflammation and Atherothrombosis

Puneetpal Singh et al. Vaccines (Basel). .

Abstract

Atherosclerosis is the formation of plaque within arteries due to overt assemblage of fats, cholesterol and fibrous material causing a blockage of the free flow of blood leading to ischemia. It is harshly impinging on health statistics worldwide because of being principal cause of high morbidity and mortality for several diseases including rheumatological, heart and brain disorders. Atherosclerosis is perpetuated by pro-inflammatory and exacerbated by pro-coagulatory mediators. Besides several other pathways, the formation of neutrophil extracellular traps (NETs) and the activation of the NOD-like receptor family pyrin domain containing 3 (NLRP3) inflammasome contribute significantly to the initiation and propagation of atherosclerotic plaque for its worst outcomes. The present review highlights the contribution of these two disturbing processes in atherosclerosis, inflammation and atherothrombosis in their individual as well as collaborative manner.

Keywords: NLRP3 inflammasome; atherosclerosis; atherothrombosis; inflammation; macrophages; monocytes; neutrophil extracellular traps; neutrophils.

PubMed Disclaimer

Conflict of interest statement

The authors declare no conflict of interest. The funding agency has no role in the design of the study; in the collection, analyses or interpretation of data; in the writing of the manuscript; or in the decision to publish the results.

Figures

Figure 1
Figure 1
Initiation of atherosclerosis (A), progression (B) and rupture of atherosclerotic plaque (C).
Figure 2
Figure 2
Overview of suicidal NETosis. Cholesterol crystals interact with free radicals and generate NADPH-oxidase-induced reactive oxygen species (ROS). ROS stimulate peptidyl arginine deiminase 4 (PADI4) to citrullinate arginine resulting in loosening of chromatin from histone. Myeloperoxidase (MPO) and neutrophil elastase (NE) migrate to the nuclear membrane for its rupturing by further decondensation of the chromatin. This decondensed chromatin exhibits a mesh-like structure called neutrophil extracellular trap (NET), which is ejected into the cytoplasm, where it is embedded with azurophilic granules and cytosolic proteins. Finally, this NET is ejected through the membrane rupturing of the neutrophil and causing its death.
Figure 3
Figure 3
NLRP3 inflammasome activation. Cholesterol crystals are internalized by CD36 and taken by phagosomes for phagocytosis. Cholesterol crystals are broken down and lysosomes attach to phagosomes to form phagolysosomes. Because of the size and chemistry of the cholesterol crystals, the phagolysosome ruptures and undegraded crystals along with cathepsin B are exposed in cytoplasm. This is the priming signal for NLRP3 inflammasome activation. Other signals such as K+ efflux, Ca2+ influx and lipopolysaccharide (LPS) may also trigger the NLRP3 inflammasome. Immature forms of IL-1β and IL-18 (pro-IL-1β and pro-Il-18) are proteolytically cleaved by activated caspase-1. These mature cytokines IL-1β and IL-18 are released into the extra cellular space by pore-forming Gasdermin D.
Figure 4
Figure 4
Neutrophil-macrophage crosstalk for mutually inciting atherosclerosis and igniting inflammation. Components of NETs (dead mitochondria and cfDNA) prime macrophages and components of NLRP3 inflammasome activation (IL-1β and IL-18) induce neutrophils to form NETs. Cholesterol crystals evoke signals for both neutrophils and macrophages for the development of NETs and prime NLRP3 inflammasome by interacting with reactive oxygen species (ROS) and CD36-mediated internalization, respectively.
See this image and copyright information in PMC

References

    1. Libby P., Buring J.E., Badimon L., Hansson G.K., Deanfield J., Bittencourt M.S., Tokgözoğlu L., Lewis E.F. Atherosclerosis. Nat. Rev. Dis. Primers. 2019;5:56. doi: 10.1038/s41572-019-0106-z. - DOI - PubMed
    1. Lechner K., von Schacky C., McKenzie A.L., Worm N., Nixdorff U., Lechner B., Kränkel N., Halle M., Krauss R.M., Scherr J. Lifestyle factors and high-risk atherosclerosis: Pathways and mechanisms beyond traditional risk factors. Eur. J. Prev. Cardiol. 2020;27:394–406. doi: 10.1177/2047487319869400. - DOI - PMC - PubMed
    1. Tabas I., García-Cardeña G., Owens G.K. Recent insights into the cellular biology of atherosclerosis. J. Cell. Biol. 2015;209:13–22. doi: 10.1083/jcb.201412052. - DOI - PMC - PubMed
    1. Kong P., Cui Z.-Y., Huang X.-F., Zhang D.-D., Guo R.-J., Han M. Inflammation and atherosclerosis: Signaling pathways and therapeutic intervention. Signal Transduct. Target. Ther. 2022;7:131. doi: 10.1038/s41392-022-00955-7. - DOI - PMC - PubMed
    1. Dabagh M., Jalali P., Tarbell J.M. The transport of LDL across the deformable arterial wall: The effect of endothelial cell turnover and intimal deformation under hypertension. Am. J. Physiol. Heart Circ. Physiol. 2009;297:H983–H996. doi: 10.1152/ajpheart.00324.2009. - DOI - PMC - PubMed

LinkOut - more resources