iBet uBet web content aggregator. Adding the entire web to your favor.
iBet uBet web content aggregator. Adding the entire web to your favor.



Link to original content: https://pubmed.ncbi.nlm.nih.gov/34183243
The NLRP3 inflammasome and COVID-19: Activation, pathogenesis and therapeutic strategies - PubMed 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
. 2021 Oct:61:2-15.
doi: 10.1016/j.cytogfr.2021.06.002. Epub 2021 Jun 18.

The NLRP3 inflammasome and COVID-19: Activation, pathogenesis and therapeutic strategies

Ni Zhao  1 , Bin Di  2 , Li-Li Xu  3
Affiliations
Review

The NLRP3 inflammasome and COVID-19: Activation, pathogenesis and therapeutic strategies

Ni Zhao et al. Cytokine Growth Factor Rev. 2021 Oct.

Abstract

Coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), exhibits a wide spectrum of clinical presentations, ranging from asymptomatic cases to severe pneumonia or even death. In severe COVID-19 cases, an increased level of proinflammatory cytokines has been observed in the bloodstream, forming the so-called "cytokine storm". Generally, nucleotide-binding oligomerization domain-like receptor containing pyrin domain 3 (NLRP3) inflammasome activation intensely induces cytokine production as an inflammatory response to viral infection. Therefore, the NLRP3 inflammasome can be a potential target for the treatment of COVID-19. Hence, this review first introduces the canonical NLRP3 inflammasome activation pathway. Second, we review the cellular/molecular mechanisms of NLRP3 inflammasome activation by SARS-CoV-2 infection (e.g., viroporins, ion flux and the complement cascade). Furthermore, we describe the involvement of the NLRP3 inflammasome in the pathogenesis of COVID-19 (e.g., cytokine storm, respiratory manifestations, cardiovascular comorbidity and neurological symptoms). Finally, we also propose several promising inhibitors targeting the NLRP3 inflammasome, cytokine products and neutrophils to provide novel therapeutic strategies for COVID-19.

Keywords: COVID-19; Inhibitor; NLRP3 inflammasomeome; Pathogenesis; SARS-CoV-2.

PubMed Disclaimer

Conflict of interest statement

The authors declare no competing financial interest.

Figures

None
Graphical abstract
Fig. 1
Fig. 1
Schematic diagram of the canonical NLRP3 inflammasome activation mechanisms. In step 1 (priming), Toll-like receptors are stimulated by PAMPs or DAMPs (such as LPS), upregulating the expression of NLRP3 inflammasome-related components such as inactive NLRP3, NEK7, pro-caspase-1, pro-IL-1β and pro-IL-18 via the NF-κB pathway. Step 2 (activation) is typically triggered by multiple stimuli in the canonical pathway, such as ATP, pore-forming toxins, viral RNA, and particulate matter. A number of molecular/cellular signaling events have been proposed as the key mechanisms of NLRP3 inflammasome activation, including K+ efflux, Ca2+ flux, ROS production, mtDNA, mitochondrial dysfunction, lysosomal rupture and chloride intracellular channel-dependent Cl− efflux. Subsequently, the oligomerization and recruitment of NLRP3, NEK7, ASC and pro-caspase-1 are initiated, leading to the maturation of pro-IL-1β/18 into IL-1β/18 and pyroptosis by the cleavage of gasdermin D.
Fig. 2
Fig. 2
Schematic diagram of NLRP3 inflammasome activation in response to SARS-CoV-2 infection. The NLRP3 inflammasome can be activated by SARS-CoV-2 infection through the following possible pathways: 1) the E protein of SARS-CoV can induce Ca2+ transport in the ERGIC/Golgi to trigger NLRP3 inflammasome activation; 2) K+ efflux and ROS production induced by the ORF3a protein of SARS-CoV activate the NLRP3 inflammasome; 3) contact of the SARS-CoV S protein with ACE2 diminishes the degradation of Ang II, resulting in Ang II accumulation, which can activate the NLRP3 inflammasome; 4) the complement cascade induced by the N protein-MBL-MASP2 axis may lead to NLRP3 inflammasome activation via different functions of C3a, C5a and MAC; and 5) the direct interaction of the SARS-CoV ORF8b protein with the NLRP3 inflammasome LRR domain may also cause inflammasome activation.
Fig. 3
Fig. 3
Schematic diagram of the NLRP3 inflammasome in COVID-19 pathogenesis and promising inhibitors. NLRP3 inflammasome activation during COVID-19 leads to the production of IL-1β/18, facilitating the formation of cytokine storm (IL-6/8/10/1RA, TNF-α and CXCL10). 1) For respiratory symptoms, proinflammatory cytokines further activate platelets, endothelial cells and neutrophils. Higher levels of neutrophils result in the escalated production of NETs, causing clot formation, endothelial damage and alveolar damage. 2) For cardiovascular symptoms, inflammatory cytokines induced by the NLRP3 inflammasome promote endothelial dysfunction, myocarditis and cardiomyocyte damage. Additionally, gut leakage, such as LPS, can exacerbate cardiac inflammation via NLRP3 inflammasome activation. 3) For neurological symptoms, cytokines can cross the BBB to enter the CNS and induce the permeation of peripheral white blood cells and monocytes. Moreover, systemic inflammation induced by the NLRP3 inflammasome leads to the formation of pathogenic fibrils, mitochondrial dysfunction and apoptosis, which can result in neurodegeneration. Promising inhibitors of the NLRP3 inflammasome, cytokine products and the neutrophil-NET axis have been shown.
See this image and copyright information in PMC

Similar articles

See all similar articles

Cited by

See all "Cited by" articles

References

    1. Zhu N., Zhang D., Wang W., Li X., Yang B., Song J., Zhao X., Huang B., Shi W., Lu R., Niu P., Zhan F., Ma X., Wang D., Xu W., Wu G., Gao G.F., Tan W. A novel coronavirus from patients with pneumonia in China, 2019. N. Engl. J. Med. 2020;382(8):727–733. doi: 10.1056/NEJMoa2001017. - DOI - PMC - PubMed
    1. C.S.G.o.t.I.C.o.T.o. Viruses The species severe acute respiratory syndrome-related coronavirus: classifying 2019-nCoV and naming it SARS-CoV-2. Nat. Microbiol. 2020;5(4):536–544. doi: 10.1038/s41564-020-0695-z. - DOI - PMC - PubMed
    1. Tan Y.J., Lim S.G., Hong W. Characterization of viral proteins encoded by the SARS-coronavirus genome. Antiviral Res. 2005;65(2):69–78. doi: 10.1016/j.antiviral.2004.10.001. - DOI - PMC - PubMed
    1. Shah A. Novel coronavirus-induced NLRP3 inflammasome activation: a potential drug target in the treatment of COVID-19. Front. Immunol. 2020;11:1021. doi: 10.3389/fimmu.2020.01021. - DOI - PMC - PubMed
    1. Nieto-Torres J.L., Verdiá-Báguena C., Jimenez-Guardeño J.M., Regla-Nava J.A., Castaño-Rodriguez C., Fernandez-Delgado R., Torres J., Aguilella V.M., Enjuanes L. Severe acute respiratory syndrome coronavirus E protein transports calcium ions and activates the NLRP3 inflammasome. Virology. 2015;485:330–339. doi: 10.1016/j.virol.2015.08.010. - DOI - PMC - PubMed

Publication types

MeSH terms

Substances