SARS-CoV-2 infection and overactivation of Nlrp3 inflammasome as a trigger of cytokine “storm” and risk factor for damage of hematopoietic stem cells
Open accessAbstract
The scientific community faces an unexpected and urgent challenge related to the SARS-CoV-2 pandemic and is investigating the role of receptors involved in entry of this virus into cells as well as pathomechanisms leading to a cytokine “storm,” which in many cases ends in severe acute respiratory syndrome, fulminant myocarditis and kidney injury. An important question is if it may also damage hematopoietic stem progenitor cells?
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During the progress of infection, ATP release may result from the NLRP3 inflammasome response to COVID-19 infection after virus spike protein interaction with ACE2, due to elevated level of Ang II observed in infected patients, or in response to activated ComC mediators.
“During the progress of infection, ATP release may result from the NLRP3 inflammasome response to COVID-19 infection (i) after virus spike protein interaction with the virus entry receptor ACE2, (ii) due to elevated level of Ang II observed in infected patients, or (iii) in response to activated ComC mediators [61].”
From Hyperactivation of P2X7 receptors as a culprit of COVID-19 neuropathology (2021) · cites this paper as [61]
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“activation in response to SARS-CoV-2 infection might lead to initiation of cytokine storm and pyroptosis in cells that include hematopoietic stem cells (37).”
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“In addition, NF-kB up-regulates IL-18 and IL-1beta expression, further increasing NLRP3 inflammasome [141,143,144], as shown in Figure 3.”
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NLRP3 inflammasome activation in COVID-19: an interlink between risk factors and disease severity
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“The concentration of 1.25–10 µg/mL of P3G was found to be able to significantly suppress the mRNA levels of NLRP3, IL-1β, and IL-18 in a dose dependent-manner (Figure 5C,D, p 0.05).”
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“Alternatively, NLRP3 inflammasome has been suggested to be activated by SARS-CoV-2 S protein [56] that is encoded by these vaccine mRNAs.”
BackgroundRole for Leptin and Leptin Receptors in Stem Cells During Health and Diseases
Trinh, T. L. P., & Broxmeyer, H. E. (2021) · Stem Cell Reviews and Reports · doi:10.1007/s12015-021-10132-y · Cited by 41 · see citing works
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Role of senescence in the chronic health consequences of COVID-19
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“NLRP3 is expressed in several cell types, as innate immunity, endothelial, haematopoietic, lung epithelial, kidney, and cardiac cells (Ratajczak & Kucia, 2020).”
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Sex-Related Overactivation of NLRP3 Inflammasome Increases Lethality of the Male COVID-19 Patients
Zhang, H., Tang, Y., & Tao, J. (2021) · Frontiers in Molecular Biosciences · doi:10.3389/fmolb.2021.671363 · Cited by 37 · see citing works
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“The majority of infected people remain asymptomatic or develop mild symptoms such as fever, cough, conjunctivitis, myalgia, fatigue and, minor neuropathies [3].”
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Declercq, J., Leeuw, E. D., & Lambrecht, B. N. (2022) · Cytokine · doi:10.1016/j.cyto.2022.155934 · Cited by 40 · see citing works
“Dysregulated activation of inflammasomes could be a trigger for the hyperinflammation seen in severe COVID-19, a hypothesis that was introduced already early after the first appearance of the virus[4].”
BackgroundRicordi, C., Pacifici, F., Lanzoni, G., Palamara, A. T., Garaci, E., & Della‐Morte, D. (2021) · International Journal of Molecular Sciences · doi:10.3390/ijms22063134 · Cited by 36 · see citing works
“SARS-CoV-2 infection has been reported to induce the over-activation of Nlrp3 inflammasome, leading to cytokine storms responsible for tissue damage and severe complications from COVID-19 [57].”
BackgroundWang, M., Chang, W., Zhang, L., & Zhang, Y. (2022) · International Journal of Biological Sciences · doi:10.7150/ijbs.77561 · Cited by 34 · see citing works
“Activation of RAAS leads to elevated levels of Ang II, which is a pivotal initiator of NLRP3 inflammasome [88].”
BackgroundMolecular mechanisms and roles of pyroptosis in acute lung injury
Wei, T., Zhang, C., & Song, Y. (2022) · Chinese Medical Journal · doi:10.1097/cm9.0000000000002425 · Cited by 37 · see citing works
Antushevich, H. (2020) · Immunology Letters · doi:10.1016/j.imlet.2020.09.004 · Cited by 33 · see citing works
“cells by binding to ACE2 only via the spike protein [44].”
Role of Exercise Intensity on Th1/Th2 Immune Modulations During the COVID-19 Pandemic
Supriya, R., Gao, Y., Gu, Y., & Baker, J. S. (2021) · Frontiers in Immunology · doi:10.3389/fimmu.2021.761382 · Cited by 34 · see citing works
Regulation and functions of the NLRP3 inflammasome in RNA virus infection
Yue, Z., Zhang, X., Gu, Y., Liu, Y., Lan, L.-M., Liu, Y., Li, Y., Yang, G., Wan, P., & Chen, X. (2024) · Frontiers in Cellular and Infection Microbiology · doi:10.3389/fcimb.2023.1309128 · Cited by 34 · see citing works
COVID-19: The Immune Responses and Clinical Therapy Candidates
Zhand, S., Jazi, M. S., Mohammadi, S., Rasekhi, R. T., Rostamian, G., Kalani, M. R., Rostamian, A., George, J., & Douglas, M. W. (2020) · International Journal of Molecular Sciences · doi:10.3390/ijms21155559 · Cited by 33 · see citing works
“NLRs are a subclass of PRRs which are comprised of a conserved NOD structure and classified into three main categories according to their functions: inflammasome (NLRP1, NLRP3, NLRP6, NLRC4, NLRC5W, and AY2); embryo regenerative and regulatory NLRs [25,41].”
BackgroundKountouri, A., Korakas, E., Ikonomidis, I., Raptis, A. E., Tentolouris, N., Dimitriadis, G., & Lambadiari, V. (2021) · Antioxidants · doi:10.3390/antiox10050752 · Cited by 33 · see citing works
Picking up a Fight: Fine Tuning Mitochondrial Innate Immune Defenses Against RNA Viruses
Dutta, S., Das, N., & Mukherjee, P. (2020) · Frontiers in Microbiology · doi:10.3389/fmicb.2020.01990 · Cited by 33 · see citing works
Cell‐mediated immunity to SARS‐CoV‐2
Wang, X., & Gui, J. (2020) · Pediatric Investigation · doi:10.1002/ped4.12228 · Cited by 31 · see citing works
“Particularly, overactivation of NOD-like receptor pyrin domaincontaining 3 (NLRP3) inflammasome promotes IL-1β and IL-18 production exacerbating the tissue damage as well as cell death of hematopoietic stem cells.(23,24) Like other viral infections, the SARS-CoV-2 antigens are processed by specific antigen presenting…”
BackgroundVariant analysis of the first Lebanese SARS-CoV-2 isolates
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“893 which in many cases end in severe symptoms leading to death [5].”
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Cardiovascular and Renal Risk Factors and Complications Associated With COVID-19
Touyz, R. M., Boyd, M. O. E., Guzik, T. J., Padmanabhan, S., McCallum, L., Delles, C., Mark, P. B., Petrie, J. R., Rios, F. J. O., Montezano, A. C. I., et al. (2021) · CJC Open · doi:10.1016/j.cjco.2021.05.020 · Cited by 31 · see citing works
“Viral infection and myocarditis in COVID-19 may also exacerbate features of cytokine storm and contribute to further heart muscle dysfunction.(67) Cardiac injury in models of viral myocarditis leads to innate immunity activation with macrophage infiltration and overproduction of proinflammatory cytokines,(68) influenc…”
Protection by metformin against severe Covid-19: An in-depth mechanistic analysis
Wiernsperger, N. F., Al‐Salameh, A., Cariou, B., & Lalau, J. (2022) · Diabetes & Metabolism · doi:10.1016/j.diabet.2022.101359 · Cited by 30 · see citing works
“The NLRP3 inflammasome (which is overactivated in Covid-19) is largely responsible for the cytokine storm [39].”
Hypothesis: Pentoxifylline is a potential cytokine modulator therapeutic in COVID‐19 patients
Hendry, B. M., Stafford, N., Arnold, A. D., Sangwaiya, A., Manglam, V., Rosen, S. D., & Arnold, J. (2020) · Pharmacology Research & Perspectives · doi:10.1002/prp2.631 · Cited by 29 · see citing works
Innate Immune Response and Inflammasome Activation During SARS-CoV-2 Infection
Islamuddin, M., Mustfa, S. A., Ullah, S. N. M. N., Omer, U., Kato, K., & Parveen, S. (2022) · Inflammation · doi:10.1007/s10753-022-01651-y · Cited by 29 · see citing works
“In this context, it can be inferred that SARS-CoV-2 infection activates the NLRP3 inflammasome through the complement cascade pathway [108, 109].”
BackgroundNasiri, K., Mohammadzadehsaliani, S., Kheradjoo, H., Shabestari, A. M., Eshaghizadeh, P., Pakmehr, A., Alsaffar, M. F., Al-Naqeeb, B. Z. T., Yasamineh, S., & Gholizadeh, O. (2023) · Cell Communication and Signaling · doi:10.1186/s12964-023-01122-3 · Cited by 28 · see citing works
“For example, SARS-CoV-2 may, on the one hand, directly infect the pool of HSPCs, and other pathological triggers of the Nlrp3 inflammasome may result in cytokine storm and pyroptosis of these cells [59].”
BackgroundInnate and adaptive immunity to SARS-CoV-2 and predisposing factors
Shen, J., Fan, J., Zhao, Y., Jiang, D., Niu, Z., Zhang, Z., & Cao, G. (2023) · Frontiers in Immunology · doi:10.3389/fimmu.2023.1159326 · Cited by 31 · see citing works
Gastrointestinal inflammation and cancer: viral and bacterial interplay
Arrè, V., Luca, R. D., Mrmić, S., et al. (2025) · Gut Microbes · doi:10.1080/19490976.2025.2519703 · Cited by 27 · see citing works
Chen, W., Li, X., Liu, X., Lin, Y., Tang, Q., & Meng, F. (2021) · Current Gene Therapy · doi:10.2174/1566523221666210907162005 · Cited by 27 · see citing works
Genetic and non-genetic risk factors associated with atrial fibrillation
Young, L. J., Antwi-Boasiako, S., Ferrall, J., Wold, L. E., Mohler, P. J., & Refaey, M. E. (2022) · Life Sciences · doi:10.1016/j.lfs.2022.120529 · Cited by 28 · see citing works
Oncogenic potential of SARS-CoV-2—targeting hallmarks of cancer pathways
Jaiswal, A., Shrivastav, S., Kushwaha, H. R., Chaturvedi, R., & Singh, R. P. (2024) · Cell Communication and Signaling · doi:10.1186/s12964-024-01818-0 · Cited by 26 · see citing works
“Additionally, dysregulation of the RAAS can also trigger this activation, promoting the assembly and activation of the inflammasome [170, 171].”
BackgroundWu, J., Zhao, M., Li, C., Zhang, Y., & Wang, D. W. (2021) · Bioscience Reports · doi:10.1042/bsr20204201 · Cited by 26 · see citing works
The Coronavirus Disease 2019 (COVID-19): Key Emphasis on Melatonin Safety and Therapeutic Efficacy
Ramos, E., Lopez-Munoz, F. J., Gil‐Martín, E., Egea, J., Álvarez‐Merz, I., Painuli, S., Semwal, P., Martins, N. A., Hernández-Guijo, J. M., & Romero, A. (2021) · Antioxidants · doi:10.3390/antiox10071152 · Cited by 25 · see citing works
Long COVID Definition, Symptoms, Risk Factors, Epidemiology and Autoimmunity: A Narrative Review
Kozłowski, P., Leszczyńska, A., & Ciepiela, O. (2024) · American Journal of Medicine Open · doi:10.1016/j.ajmo.2024.100068 · Cited by 27 · see citing works
Lumpuy‐Castillo, J., Lorenzo-Almorós, A., Lázaro, A. M. P., Sánchez‐Ferrer, C. F., Egido, J., Tuñón, J., Peiró, C., & Lorenzo, Ó. (2020) · International Journal of Molecular Sciences · doi:10.3390/ijms21186471 · Cited by 25 · see citing works
“Also, Nucleotide-binding and oligomerization domain (NOD)-like receptors induce IL1β upregulation via the NOD-, LRR- and pyrin domain-containing protein-3 (NLRP3)-inflammasome [16].”
BackgroundPetiz, L. L., Glaser, T., Scharfstein, J., Ratajczak, M. Z., & Ulrich, H. (2021) · Stem Cell Reviews and Reports · doi:10.1007/s12015-021-10129-7 · Cited by 25 · see citing works
Self-citationHu, H., Tang, N., Zhang, F., Li, L., & Li, L. (2022) · Frontiers in Immunology · doi:10.3389/fimmu.2022.860676 · Cited by 25 · see citing works
Current Technologies and Future Perspectives in Immunotherapy towards a Clinical Oncology Approach
Adhikary, S., Pathak, S., Palani, V., Acar, A., Banerjee, A., Al-Dewik, N. I. E., Essa, M. M., Mohammed, S. G. A. A., & Qoronfleh, M. W. (2024) · Biomedicines · doi:10.3390/biomedicines12010217 · Cited by 27 · see citing works
“It is reported that upon SARS-CoV-2 infection, the inflammasome becomes active, which was found to be associated with the severity of COVID-19 patients [170], and among them, the NLRP3 inflammasome becomes more active and can promote a cytokine storm [171].”
BackgroundThe interplay of transition metals in ferroptosis and pyroptosis
Vana, F., Szabo, Z., Masařík, M., & Kratochvílová, M. (2024) · Cell Division · doi:10.1186/s13008-024-00127-9 · Cited by 24 · see citing works
ACE2 and Innate Immunity in the Regulation of SARS-CoV-2-Induced Acute Lung Injury: A Review
Qu, L., Chen, C., Yin, T., Fang, Q., Hong, Z.-Z., Zhou, R., Tang, H., & Dong, H. (2021) · International Journal of Molecular Sciences · doi:10.3390/ijms222111483 · Cited by 23 · see citing works
Cimmino, G., Conte, S., Morello, M., Pellegrino, G., Marra, L., Morello, A., Nicoletti, G., Rosa, G. D., Golino, P., & Cirillo, P. L. (2022) · Journal of Cardiovascular Development and Disease · doi:10.3390/jcdd9010027 · Cited by 24 · see citing works
“Some evidence has shown that the cytokine storm with elevated levels of IL-1 and IL-6 observed in SARS-CoV2 patients is due to the activation of NLRP3 inflammasome [22,23].”
BackgroundJutel, M., Torres, M. J., Palomares, Ó., Akdiş, C. A., Eiwegger, T., Untersmayr, E., Barber, D., Zemelka‐Wiącek, M., Kosowska, A., Palmer, E. N., et al. (2022) · Allergy · doi:10.1111/all.15252 · Cited by 24 · see citing works
Targeting autophagy regulation in NLRP3 inflammasome-mediated lung inflammation in COVID-19
Yong, Y.-Y., Zhang, L., Hu, Y.-J., Wu, J., Yan, L., Pan, Y., Tang, Y., Yu, L., Law, B. Y. K., Yu, C., et al. (2022) · Clinical Immunology · doi:10.1016/j.clim.2022.109093 · Cited by 25 · see citing works
“PYCARD, the receptor, CARD and PYD [7,8].”
InfluentialInflammasomes: a rising star on the horizon of COVID-19 pathophysiology
Wang, M., Yu, F., Chang, W., Zhang, Y., Zhang, L., & Li, P. (2023) · Frontiers in Immunology · doi:10.3389/fimmu.2023.1185233 · Cited by 24 · see citing works
“Particularly, NLRP3 inflammasome can induce host immune responses via caspase-1-dependent pyroptosis, which results in extravasation of proinflammatory cytokines (e.g., IL-1b and IL-18) and biologically active DAMPs (131).”
BackgroundInfluentialLambadiari, V., Kousathana, F., Raptis, A. E., Katogiannis, K., Kokkinos, A. D., & Ikonomidis, I. (2020) · Frontiers in Immunology · doi:10.3389/fimmu.2020.557235 · Cited by 23 · see citing works
“NLRP3 inflammasome is also triggered by SARS-CoV-2 through other pathways: a) through the proteins E, 3a, and 8b of SARS-CoV, b) after the binding of the spike protein of the virus to ACE2 receptors of pneumonocytes, c) after the activation of the renin–angiotensin– aldosterone system (RAAS) leading to elevated levels…”
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Li, S., Song, J., Liu, J., et al. (2024) · Journal of Biological Chemistry · doi:10.1016/j.jbc.2024.107307 · Cited by 22 · see citing works
Sahu, A. K., Sreepadmanabh, M., Rai, M., & Chande, A. G. (2021) · VirusDisease · doi:10.1007/s13337-021-00653-y · Cited by 22 · see citing works
Chasing COVID-19 through SARS-CoV-2 spike glycoprotein
Saxena, S. K., Kumar, S., Baxi, P., Srivastava, N., Puri, B., & Ratho, R. K. (2020) · VirusDisease · doi:10.1007/s13337-020-00642-7 · Cited by 21 · see citing works
Colchicine — From rheumatology to the new kid on the block: Coronary syndromes and COVID-19
Surma, S., Basiak, M., Romańczyk, M., Filipiak, K. J., & Okopień, B. (2021) · Cardiology Journal · doi:10.5603/cj.a2021.0123 · Cited by 21 · see citing works
“Colchicine, as an important inhibitor of the NLRP3 inflammasome, may be used in the treatment of COVID-19 [8, 40, 41].”
MethodMelatonin, Zinc, and Vitamin C: Potential Adjuvant Treatment for COVID-19 Patients
Borges, L., Gennari-Felipe, M., Dias, B. B., & Hatanaka, E. (2022) · Frontiers in Nutrition · doi:10.3389/fnut.2021.821824 · Cited by 21 · see citing works
“The SARS-CoV-2 virus stimulates the nod-like receptor family, pyrin domain-containing three inflammasome (29), activating nuclear factor kappa-B (NF-κB) and resulting in cytokines expression and release (30), and leukocyte dysfunction (31).”
BackgroundWang, Y., Wu, M., Li, Y., Yuen, H. H., & He, M. (2022) · Journal of Biomedical Science · doi:10.1186/s12929-022-00811-4 · Cited by 22 · see citing works
“The last pathway is the recognition and activation of the complement cascade (ComC) through the Mannan-binding lectin (MBL)/MBL-associated serine protease-2 (MASP2) complex, leading to the release of ComC cleavage fragment (C3a and C5a) and the C5b/C9 membrane attack complex (MAC) that activate NLRP3 [36].”
BackgroundKullappan, M., Mary, U., Ambrose, J. M., Veeraraghavan, V. P., & Surapaneni, K. M. (2021) · Journal of Biomolecular Structure and Dynamics · doi:10.1080/07391102.2021.2014973 · Cited by 20 · see citing works
- Authors
- Ratajczak, M. Z., & Kucia, M.
- Affiliations
- University of Louisville (US)
- Corresponding author
- Ratajczak, Mariusz Z.
- Venue
- Leukemia
- Published
- 2020-06-01
- Volume
- 34
- Issue
- 7
- Pages
- 1726-1729
- ISSN
- 0887-6924 (ISSN-L)
- 1476-5551
- PMC
- PMC7262681
- OpenAlex
- W3031438965
- Semantic Scholar
- 21891a793cf57a44dca049798218b329c5014a35
- Cited by
- 235
- References
- 16
- Citations by year
- 2026: 7 · 2025: 17 · 2024: 26 · 2023: 26 · 2022: 57 · 2021: 69 · 2020: 33
- FWCI
- 15.09
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Locations
- Leukemia (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Funders
- U.S. Department of Health & Human Services | NIH | National Institute of Diabetes and Digestive and Kidney Diseases (2R01 DK074720)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Inflammasome and immune disorders
- Health Sciences › Medicine › Infectious Diseases › COVID-19 Clinical Research Studies
- Health Sciences › Medicine › Hematology › Autoimmune and Inflammatory Disorders Research
- Keywords
- SARS-CoV-2, NLRP3 inflammasome, cytokine storm, hematopoietic stem cells, COVID-19 pathogenesis, myocarditis, kidney injury, viral entry receptor
- MeSH terms
- Pyroptosis, NLR Family, Pyrin Domain-Containing 3 Protein, Betacoronavirus, Cytokine Release Syndrome, Angiotensin-Converting Enzyme 2, COVID-19, SARS-CoV-2, Furans, Gene Expression Regulation, Hematopoietic Stem Cells, Heterocyclic Compounds, 4 or More Rings, Humans, Immunity, Innate, Immunologic Factors, Indenes, Peptidyl-Dipeptidase A, Myocarditis, Pneumonia, Viral, Risk Factors, Sulfonamides, Sulfones, T-Lymphocytes, Cytokines, Coronavirus Infections, Severe Acute Respiratory Syndrome, Acute Kidney Injury, Inflammasomes, Pandemics, Spike Glycoprotein, Coronavirus
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