NLRP3 inflammasome And COVID-19

The inflammasome is a macromolecular protein signalling complex that takes part in the regulation of the activation of caspase 1 and the generation and secretion of pro-inflammatory cytokines such as IL-18 and IL-1β and leads off an inflammatory process in response to various stress factors, exogenous agents including microorganisms, and endogenous danger signals 1 2 3. It is a kind of inflammatory immune response and is created in the cytosolic compartment in reply to the endogenous danger signals 2. A member of nucleotide-binding oligomerization domain-containing protein NOD-like receptor (NLR) protein functions as a sensing component of inflammasome 2 4. One of the most characterized of inflammasomes, belonging to the NLR protein family, is Nod-like receptor protein 3 (NLRP3) and it comprises 22 members in homo sapiens 5 6. NLRP3 inflammasome is also known as pyrin domain-containing protein 3 7.

NLRP3 is one of the large cytosolic protein complexes called inflammasome and plays role in the initiation, division, and activation of procaspase-1 in humans that gives rise to the proteolytic activation of pro-IL-1β and pro-IL-18 cytokines 6. Lysosomal destabilization or decline in the concentration of intracellular K+ are sensed by NLRP3 as danger signal 1. When lysosomal machinery can not digest an either microbial or nonmicrobial pathogen, it causes activation of secondary defense mechanism. In consequence, leakage of cathepsin B into the cytoplasm and K+ efflux from the cell occurs. Induction of the NLRP3’s conformational change elicits 1.

Figure 1:8 NLRP3 inflammasome formation pathways

NLRP3 inflammasome provides host immune defence against fungal, bacterial, and viral infections 9. Dysregulation of the NLRP3 inflammasome results in the pathogenesis of several inflammatory disorders such as Alzheimer’s disease, autoinflammatory diseases, cryopyrin-associated periodic syndromes (CAPS) which is an autoinflammatory syndrome formed due to heterozygous mutations of the NLRP gene [1], diabetes, and atherosclerosis 10 11. NLRP3 reacts to various inflammatory infectious and endogenous ligands including pathogen-associated molecular patterns (PAMPs) and/or damage-associated molecular patterns (DAMPs) 12 13.

NLRP3 INFLAMMASOME in SEVERE COVID-19

 

Figure 3: 14 NLRP3 inflammasome mediates lung inflammation in SARS-Cov-2 infection.

SARS-CoV-2 causes the activation of the purinergic receptor P2X 7 (P2RX7) by a discharge of extracellular ATP. The P2RX7 signalling has the potential to give rise to activation of NLRP3 via directly or indirectly activating in activated macrophages. Lung inflammation in SARS-CoV-2 infection is mediated by the NLRP3 inflammasome 14. Activation of the NLRP3 inflammasome mediates the release of IL-1β and IL-18 and pyroptosis that is the inflammatory form of regulated cell death which requires Caspase 1 activation happens 15.  Activated macrophages give rise to a cascade of massive inflammatory cytokine activation involving TNF-α, IL-6, IL-1RA, IL-8, IL-10, and CXCL10 14.  Acute lung injury with acute respiratory distress syndrome which gives rise to respiratory failure, systemic inflammatory response syndrome (SIRS), shock and multiorgan dysfunction, and coagulopathy that is a prevalent characteristic of SARS-CoV-2 infection ensues 14 16 17.

NLRP3 INFLAMMASOME COMPLEX ACTIVATION

 

Figure 2: 2 Activation and signaling of NLRP3 inflammasome

Expression of NLRP3 complex in immune cells particularly inflammatory cells occurs after the presence of inflammatory stimulatory triggers including macrophages (a potent APC), dendritic cells (DC), neutrophils in monocytes, and the spleen 18. The two-hit hypothesis has been introduced for NLRP3 activation 19. Exposure to PAMPs and/or DAMPs causes auto-phosphorylation of Toll-like receptors (TLRs) and results in activation of nuclear factor-κB (NF-κB), it is the initial hit 2. Stimulation of the transcription and the expression of NLRP3 inflammasome components, pro-IL-1β, and pro-IL-18 that stay inactive after being translocated to cytoplasm until the second hit takes place by activation of NF-κB 20. The second hit provides oligomerization of the inactive inflammasome complex (NLRP3, ASC, and caspase-1) and activation, maturation, and up-regulation of IL-1β which is a pro-inflammatory cytokine,  and recruits the native immune cells to the infected area and IL-18 which is important for the formation of interferon-γ (IFN-γ), and enhances the activity of natural killer (NK) cells and T cells result in 19 21 22.

          REFERENCES:

  1. Toldo S, Mezzaroma E, Mauro AG, Salloum F, Van Tassell BW, Abbate A. The Inflammasome in Myocardial Injury and Cardiac Remodeling. Antioxidants Redox Signal. Published online 2015. doi:10.1089/ars.2014.5989
  2. Moossavi M, Parsamanesh N, Bahrami A, Atkin SL, Sahebkar A. Role of the NLRP3 inflammasome in cancer. Mol Cancer. Published online 2018. doi:10.1186/s12943-018-0900-3
  3. Zhen Y, Zhang H. NLRP3 inflammasome and inflammatory bowel disease. Front Immunol. Published online 2019. doi:10.3389/fimmu.2019.00276
  4. Sutterwala FS, Haasken S, Cassel SL. Mechanism of NLRP3 inflammasome activation. Ann N Y Acad Sci. Published online 2014. doi:10.1111/nyas.12458
  5. Ting JPY, Lovering RC, Alnemri ESPD, et al. The NLR gene family: An official nomenclature. Immunity. Published online 2008.
  6. Place DE, Kanneganti TD. Recent advances in inflammasome biology. Curr Opin Immunol. Published online 2018. doi:10.1016/j.coi.2017.10.011
  7. Eigenbrod T, Dalpke AH. Bacterial RNA: An Underestimated Stimulus for Innate Immune Responses. J Immunol. Published online 2015. doi:10.4049/jimmunol.1500530
  8. Toldo S, Abbate A. The NLRP3 inflammasome in acute myocardial infarction. Nat Rev Cardiol. Published online 2018. doi:10.1038/nrcardio.2017.161
  9. Thomas PG, Dash P, Aldridge JR, et al. The Intracellular Sensor NLRP3 Mediates Key Innate and Healing Responses to Influenza A Virus via the Regulation of Caspase-1. Immunity. Published online 2009. doi:10.1016/j.immuni.2009.02.006
  10. Menu P, Vince JE. The NLRP3 inflammasome in health and disease: The good, the bad and the ugly. Clin Exp Immunol. Published online 2011. doi:10.1111/j.1365-2249.2011.04440.x
  11. Guo H, Callaway JB, Ting JPY. Inflammasomes: Mechanism of action, role in disease, and therapeutics. Nat Med. Published online 2015. doi:10.1038/nm.3893
  12. Sharma D, Kanneganti TD. The cell biology of inflammasomes: Mechanisms of inflammasome activation and regulation. J Cell Biol. Published online 2016. doi:10.1083/jcb.201602089
  13. Lamkanfi M, Dixit VM. Inflammasomes and their roles in health and disease. Annu Rev Cell Dev Biol. Published online 2012. doi:10.1146/annurev-cellbio-101011-155745
  14. Freeman TL, Swartz TH. Targeting the NLRP3 Inflammasome in Severe COVID-19. Front Immunol. Published online 2020. doi:10.3389/fimmu.2020.01518
  15. Miller DR, Cramer SD, Thorburn A. The interplay of autophagy and non-apoptotic cell death pathways. In: International Review of Cell and Molecular Biology. ; 2020. doi:10.1016/bs.ircmb.2019.12.004
  16. Wood C, Kataria V, Modrykamien AM. The acute respiratory distress syndrome. Baylor Univ Med Cent Proc. Published online 2020. doi:10.1080/08998280.2020.1764817
  17. Iba T, Levy JH, Levi M, Connors JM, Thachil J. Coagulopathy of Coronavirus Disease 2019. Crit Care Med. Published online 2020. doi:10.1097/CCM.0000000000004458
  18. Zhong Y, Kinio A, Saleh M. Functions of NOD-Like Receptors in Human Diseases. Front Immunol. Published online 2013. doi:10.3389/fimmu.2013.00333
  19. Ozaki E, Campbell M, Doyle SL. Targeting the NLRP3 inflammasome in chronic inflammatory diseases: Current perspectives. J Inflamm Res. Published online 2015. doi:10.2147/JIR.S51250
  20. Franchi L, Eigenbrod T, Muñoz-Planillo R, et al. Cytosolic Double-Stranded RNA Activates the NLRP3 Inflammasome via MAVS-Induced Membrane Permeabilization and K + Efflux . J Immunol. Published online 2014. doi:10.4049/jimmunol.1400582
  21. He Y, Hara H, Núñez G. Mechanism and Regulation of NLRP3 Inflammasome Activation. Trends Biochem Sci. Published online 2016. doi:10.1016/j.tibs.2016.09.002
  22. Kim EH, Park MJ, Park S, Lee ES. Increased expression of the NLRP3 inflammasome components in patients with Behçet’s disease. J Inflamm (United Kingdom). Published online 2015. doi:10.1186/s12950-015-0086-z

 Figure Referance:

  1. Toldo S, Abbate A. The NLRP3 inflammasome in acute myocardial infarction. Nat Rev Cardiol. Published online 2018. doi:10.1038/nrcardio.2017.161
  2. Moossavi M, Parsamanesh N, Bahrami A, Atkin SL, Sahebkar A. Role of the NLRP3 inflammasome in cancer. Mol Cancer. Published online 2018. doi:10.1186/s12943-018-0900-3
  3.  Freeman TL, Swartz TH. Targeting the NLRP3 Inflammasome in Severe COVID-19. Front Immunol. Published online 2020. doi:10.3389/fimmu.2020.

Inspector:Meryem Melisa KAR

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