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COVID-19 cytokine storm: The anger of inflammation
Open accessAbstract
Patients with COVID-19 who require ICU admission might have the cytokine storm. It is a state of out-of-control release of a variety of inflammatory cytokines. The molecular mechanism of the cytokine storm has not been explored extensively yet. The attachment of SARS-CoV-2 spike glycoprotein with angiotensin-converting enzyme 2 (ACE2), as its cellular receptor, triggers complex molecular events that leads to hyperinflammation. Four molecular axes that may be involved in SARS-CoV-2 driven inflammatory cytokine overproduction are addressed in this work. The virus-mediated down-regulation of ACE2 causes a burst of inflammatory cytokine release through dysregulation of the renin-angiotensin-aldosterone system (ACE/angiotensin II/AT1R axis), attenuation of Mas receptor (ACE2/MasR axis), increased activation of [des-Arg9]-bradykinin (ACE2/bradykinin B1R/DABK axis), and activation of the complement system including C5a and C5b-9 components. The molecular clarification of these axes will elucidate an array of therapeutic strategies to confront the cytokine storm in order to prevent and treat COVID-19 associated acute respiratory distress syndrome.
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“Among them, IL-6 is a major player in chronic inflammatory diseases, autoimmune diseases, cancer and cytokine storm (1, 3, 10–26).”
From IL-6 in inflammation, autoimmunity and cancer (2021) · cites this paper as [13]
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“Therefore, SARS-CoV-1 and SARS-CoV-2 infection activate both NF-κB and STAT3, key elements of the IL-6 Amp, to cause cytokine storm (12, 13, 15, 349, 350).”
From IL-6 in inflammation, autoimmunity and cancer (2021) · cites this paper as [13]
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“ARDS in COVID-19 is considered the result of cytokine storm (12–17), resembling the disease caused by SARS-CoV-1 and Middle East respiratory syndrome coronavirus (MERS-CoV) (335).”
From IL-6 in inflammation, autoimmunity and cancer (2021) · cites this paper as [13]
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“Consistent with the notion that severe COVID-19 is a cytokine storm syndrome (12–17, 336), the severity of COVID-19 is associated with an increased level of inflammatory cytokines, such as IL-6, granulocyte macrophage colony-stimulating factor (GM-CSF) and TNFα (333, 337).”
From IL-6 in inflammation, autoimmunity and cancer (2021) · cites this paper as [13]
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A Review on the Neurological Manifestations of COVID-19 Infection: a Mechanistic View
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Ramos, S. G., Rattis, B. A. D. C., Giulia Ottaviani, M., Celes, M. R. N., & Dias, E. P. (2021) · American Journal Of Pathology · doi:10.1016/j.ajpath.2021.04.010 · Cited by 59
“0 DTD AJPA3566_proof overactivation, and inflammation.(12,15,65) In addition, after AT1R activation, Ang II can activate the NF-kB pathway(66,67) via stimulation of the phosphorylation of the p65 subunit of NF-kB.”
The pivotal link between ACE2 deficiency and SARS-CoV-2 infection: One year later
Angeli, F., Zappa, M., Reboldi, G., Trapasso, M., Cavallini, C., Spanevello, A., & Verdecchia, P. (2021) · European Journal of Internal Medicine · doi:10.1016/j.ejim.2021.09.007 · Cited by 58
“of Ang II develop an abnormal activation of the Ang II/Ang II type 1 receptor (AT1R) component of the RAAS, producing end-organ damage through the activation of pro-inflammatory cascade (also enhanced by the activation of the complement system by pattern recognition receptors [PRRs]), pro-fibrotic cascade, pro-coagula…”
SARS-CoV-2 involvement in central nervous system tissue damage
Sabra, M., Kobeissy, F. H., Bizri, M., Haidar, M. A., Shakkour, Z., Reslan, M. A., Al-Haj, N., Chamoun, P., Habashy, K. J., Kaafarani, H., et al. (2021) · Neural Regeneration Research · doi:10.4103/1673-5374.327323 · Cited by 58
“Furthermore, immobilization, which is known to increase the risk of thrombus formation, is another factor that contributes to blood stasis in hospitalized COVID-19 patients (Maier et al., 2020).”
BackgroundInfluentialAltered gut microbial metabolites could mediate the effects of risk factors in Covid‐19
Chen, J., Hall, S., & Vitetta, L. (2021) · Reviews in Medical Virology · doi:10.1002/rmv.2211 · Cited by 55
“Activation of the complements C5a and C5b‐9 is also involved in SARS‐CoV‐2‐caused inflammation.(25) Guo et al.”
BackgroundEndotheliopathy in Acute COVID-19 and Long COVID
Vassiliou, A. G., Vrettou, C. S., Keskinidou, C., Dimopoulou, I., Kotanidou, Α., & Orfanos, S. E. (2023) · International Journal of Molecular Sciences · doi:10.3390/ijms24098237 · Cited by 55
AlKhafaji, D., Argan, R. A., Albaker, W., Elq, A. A., Al-Hariri, M., AlSaid, A., Alwaheed, A., Alqatari, S. G., Alzaki, A., Alwarthan, S., et al. (2022) · International Journal of General Medicine · doi:10.2147/ijgm.s346169 · Cited by 54
“One of the hallmarks of COVID-19 infection severity is the huge secretion of inflammatory cytokines known as a “cytokine storm”.(43) According to a previous report showing that respiratory illnesses are associated with dysregulated Vit D metabolism, suggesting the possibility of Vit D deficiency as a consequence of pu…”
BackgroundOkagu, I. U., Ezeorba, T. P. C., Aham, E. C., Aguchem, R. N., & Nechi, R. N. (2022) · Food Chemistry Molecular Sciences · doi:10.1016/j.fochms.2022.100078 · Cited by 54
Şehirli, A. Ö., Sayıner, S., & Serakıncı, N. (2020) · Molecular Biology Reports · doi:10.1007/s11033-020-05830-8 · Cited by 51
Dynamic Changes of Lymphocyte Subsets in the Course of COVID-19
Rezaei, M. S., Marjani, M., Mahmoudi, S., Mortaz, E., & Mansouri, D. (2021) · International Archives of Allergy and Immunology · doi:10.1159/000514202 · Cited by 51
Neutrophil Extracellular Traps in Fatal COVID-19-Associated Lung Injury
Obermayer, A., Jakob, L.-M., Haslbauer, J. D., Matter, M. S., Tzankov, A., & Stoiber, W. (2021) · Disease Markers · doi:10.1155/2021/5566826 · Cited by 56
“A copious release of proinflammatory peptides causing a cytokine storm, as seen in COVID-19 [9], has long been regarded as a potent inductor of NETosis (e.”
BackgroundNashiry, M. A., Sumi, S. S., Islam, S., Quinn, J. M. W., & Moni, M. A. (2020) · Briefings in Bioinformatics · doi:10.1093/bib/bbaa426 · Cited by 50
Lordan, R. (2021) · Nutrients · doi:10.3390/nu13030740 · Cited by 50
Autoinflammatory Diseases and Cytokine Storms—Imbalances of Innate and Adaptative Immunity
Marcuzzi, A., Melloni, E., Zauli, G., Romani, A., Secchiero, P., Maximova, N., & Rimondi, E. (2021) · International Journal of Molecular Sciences · doi:10.3390/ijms222011241 · Cited by 52
Depressive and Neurocognitive Disorders in the Context of the Inflammatory Background of COVID-19
Dąbrowska, E., Galińska-Skok, B., & Waszkiewicz, N. (2021) · Life · doi:10.3390/life11101056 · Cited by 47
A double edged-sword - The Complement System during SARS-CoV-2 infection
Santiesteban-Lores, L. E., Amamura, T. A., da Silva, T. F., Midon, L. M., Carneiro, M. C., Isaac, L., & Bavia, L. (2021) · Life Sciences · doi:10.1016/j.lfs.2021.119245 · Cited by 47
Are Nutraceuticals Effective in COVID-19 and Post-COVID Prevention and Treatment?
Catalano, A. A., Iacopetta, D., Ceramella, J., Maio, A. C. D., Basile, G., Giuzio, F., Bonomo, M. G., Aquaro, S., Walsh, T. J., Sinicropi, M. S., et al. (2022) · Foods · doi:10.3390/foods11182884 · Cited by 48
Complement Activation via the Lectin and Alternative Pathway in Patients With Severe COVID-19
Niederreiter, J., Eck, C., Ries, T., Hartmann, A., Märkl, B., Büttner-Herold, M. J., Amann, K., & Daniel, C. (2022) · Frontiers in Immunology · doi:10.3389/fimmu.2022.835156 · Cited by 49
Gasparello, J., Finotti, A., & Gambari, R. (2020) · Medical Hypotheses · doi:10.1016/j.mehy.2020.110415 · Cited by 48
“In COVID-19 cytokine storm, this perturbation is initiated via attachment of the SARS-CoV-2 spike protein to ACE2 receptor, followed by the ACE/Ang II/AT1R axis activation leading to hyperactivation of NF-κB by IL-6/STATs axis [3].”
IL 33 Correlates With COVID-19 Severity, Radiographic and Clinical Finding
Marković, S. S., Jovanovic, M., Gajović, N., Jurišević, M., Arsenijević, N., Jovanović, M., Jovanovic, M., Mijailović, Ž., Lukić, S., Zornić, N., et al. (2021) · Frontiers in Medicine · doi:10.3389/fmed.2021.749569 · Cited by 45
Du, H., Hou, X., Yujie, G., Le, C., Yu-Huan, M., Dahui, L., & Luqi, H. (2022) · Animal Models and Experimental Medicine · doi:10.1002/ame2.12224 · Cited by 45
Prognostic bioindicators in severe COVID-19 patients
Bergantini, L., Bargagli, E., d’Alessandro, M., Refini, R. M., Cameli, P., Galasso, L., Scapellato, C., Montagnani, F., Scolletta, S., Franchi, F., et al. (2021) · Cytokine · doi:10.1016/j.cyto.2021.155455 · Cited by 44
“The severe pneumonia-associated respiratory syndrome caused by the new coronavirus shows different clinical phenotypes, varying from mild-moderate to severe and critical with acute respiratory distress syndrome, requiring hospitalization and mechanical ventilation [5,6,44].”
BackgroundRavichandran, R., Surapaneni, K. M., Sukumaran, S. K., Kamaraj, D., Daivasuga, S. S., Ravi, S. O. A. S., Vijayaraghavalu, S., & Kumar, R. K. (2022) · Scientific Reports · doi:10.1038/s41598-022-10370-1 · Cited by 44
Vetrici, M. A., Mokmeli, S., Bohm, A. R., Monici, M., & Sigman, S. A. (2021) · Journal of Inflammation Research · doi:10.2147/jir.s301625 · Cited by 45
Barreiro-Sisto, U., Fernández‐Fariña, S., Noya, A. M. G., Pedrido, R. M., & Maneiro, M. (2024) · International Journal of Molecular Sciences · doi:10.3390/ijms25031892 · Cited by 50
Role of Kinins in Hypertension and Heart Failure
Hamid, S., Rhaleb, I. A., Kassem, K. M., & Rhaleb, N. (2020) · Pharmaceuticals · doi:10.3390/ph13110347 · Cited by 43
Feng, Z., Yang, J., Xu, M., Lin, R., Yang, H., Lai, L., Wang, Y., Wahner‐Roedler, D. L., Zhou, X., Shin, K.-M., et al. (2021) · Clinical Nutrition ESPEN · doi:10.1016/j.clnesp.2021.05.018 · Cited by 43
Chomiak, A. A., Tiedemann, R. L., Liu, Y., Kong, X., Cui, Y., Wiseman, A. K., Thurlow, K. E., Cornett, E. M., Topper, M. J., Baylin, S. B., et al. (2024) · Science Advances · doi:10.1126/sciadv.adk4423 · Cited by 44
Haghpanah, A., Masjedi, F., Salehipour, M., Hosseinpour, A., Roozbeh, J., & Dehghani, A. (2021) · Prostate Cancer and Prostatic Diseases · doi:10.1038/s41391-021-00388-3 · Cited by 41
“Moreover, Ang (1–7) seems to have anti-inflammatory effects through suppressing the NF-κB pathway and cytokines such as IL-6, tumor necrosis factor (TNF)-α, and IL-8 [41, 42].”
BackgroundSelf-citationCommonalities Between COVID-19 and Radiation Injury
Rios, C. I., Cassatt, D. R., Hollingsworth, B. A., Satyamitra, M. M., Tadesse, Y., Taliaferro, L. P., Winters, T. A., & DiCarlo, A. L. (2020) · Radiation Research · doi:10.1667/rade-20-00188.1 · Cited by 43
The Immunopathological and Histological Landscape of COVID-19-Mediated Lung Injury
Zarrilli, G., Angerilli, V., Businello, G., Sbaraglia, M., Traverso, G., Fortarezza, F., Rizzo, S., Gaspari, M. D., Basso, C., Calabrese, F., et al. (2021) · International Journal of Molecular Sciences · doi:10.3390/ijms22020974 · Cited by 46
Air Pollution and COVID-19: A Possible Dangerous Synergy for Male Fertility
Montano, L., Donato, F., Bianco, P. M., Lettieri, G., Guglielmino, A., Motta, O., Bonapace, I. M., & Piscopo, M. (2021) · International Journal of Environmental Research and Public Health · doi:10.3390/ijerph18136846 · Cited by 41
“One of these, IL-6, induced by Sars-CoV-2, can cause leukocyte infiltration into the testis with disruption of the testis−blood barrier that can lead to an autoimmune response with potential formation of antisperm antibodies (ASA) [80,81].”
BackgroundMahmud, M. S., Hossain, M. S., Ahmed, A. T. M. F., Islam, M. Z., Sarker, M. E., & Islam, M. R. (2021) · Molecules · doi:10.3390/molecules26237216 · Cited by 46
Lumbers, E. R., Head, R. J., Smith, G. R., Delforce, S. J., Jarrott, B., Martin, J. H., & Pringle, K. G. (2022) · Pharmacology Research & Perspectives · doi:10.1002/prp2.917 · Cited by 39
SARS-CoV-2 early infection signature identified potential key infection mechanisms and drug targets
Li, Y., Duche, A., Sayer, M. R., Roosan, D., Khalafalla, F. G., Ostrom, R. S., Totonchy, J. E., & Roosan, M. R. (2021) · BMC Genomics · doi:10.1186/s12864-021-07433-4 · Cited by 47
Dysregulated Bradykinin: Mystery in the Pathogenesis of COVID-19
Tabassum, A., Iqbal, M. S., Sultan, S., Alhuthali, R. A., Alshubaili, D. I., Sayyam, R. S., Abyad, L. M., Qasem, A. H., & Arbaeen, A. F. (2022) · Mediators of Inflammation · doi:10.1155/2022/7423537 · Cited by 38
“Many complex inflammatory molecular pathways of downregulation of angiotensin-converting enzyme 2 (ACE2) in relation to SARS-CoV-2 have been proposed, like the complement system pathway, dysregulated bradykinin pathway, angiotensin-converting enzyme/angiotensin-II/ angiotensin receptor 1 (ACE2/Ang-II/ATR1), and ACE2/…”
BackgroundKong, L., You, R., Zhang, D., Yuan, Q., Xiang, B., Liang, J., Lin, Q., Ding, C., Liao, M., Chen, L., et al. (2022) · Frontiers in Veterinary Science · doi:10.3389/fvets.2021.824179 · Cited by 38
Zheng, J., Lu, C., Ding, Y., Zhang, J., Tan, F., Liu, J., Yang, G., Wang, Y., Li, Z., Yang, M., et al. (2022) · International Journal of Pharmaceutics · doi:10.1016/j.ijpharm.2022.121719 · Cited by 37
“Coronavirus infectious disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), an increasingly prevalent viral contagion at the global scale, causes acute respiratory distress syndrome (ARDS)(Mahmudpour et al., 2020; Mohanty et al., 2021).”
Functional and druggability analysis of the SARS-CoV-2 proteome
Cavasotto, C. N., Sánchez‐Lamas, M., & Maggini, J. (2020) · European Journal of Pharmacology · doi:10.1016/j.ejphar.2020.173705 · Cited by 38
Chaves, O. A., Lima, C. R., Rodrigues, N. F., Sacramento, C. Q., de Freitas, C. S., Vázquez, L., Temerozo, J. R., Rocha, M. E. N., Dias, S. D. S. G., Carels, N., et al. (2022) · International Journal of Biological Macromolecules · doi:10.1016/j.ijbiomac.2022.09.204 · Cited by 39
“Severe cases of COVID-19 have been characterized by developing cytokine storm [35], therefore, the discovery of antivirals that also might inhibit the hyperinflammatory response and/or regulate the immune responses is an interesting strategy to better attenuate illness in patients infected with SARS-CoV-2.”
BackgroundTurrubiates‐Hernández, F. J., Sánchez‐Zuno, G. A., González-Estévez, G., Hernández‐Bello, J., Ojeda, G. M., & Muñóz-Valle, J. F. (2021) · International Journal of Molecular Medicine · doi:10.3892/ijmm.2021.4865 · Cited by 38
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 36
“Both renin-angiotensinaldosterone system (RAAS) and complement cascade are involved in SARS-CoV-2-induced overproduction of inflammatory cytokines (Mahmudpour et al., 2020), and this overproduction is caused by NLRP3 inflammasome (Ratajczak and Kucia, 2020).”
BackgroundHyperbaric oxygen treatment for long coronavirus disease-19: a case report
Bhaiyat, A. M., Sasson, E., Wang, Z., Khairy, S., Ginzarly, M., Qureshi, U., Fikree, M., & Efrati, S. (2022) · Journal of Medical Case Reports · doi:10.1186/s13256-022-03287-w · Cited by 37
Saleki, K., Banazadeh, M., Miri, N. S., & Azadmehr, A. (2021) · Reviews in the Neurosciences · doi:10.1515/revneuro-2021-0047 · Cited by 37
“…G-CSF, TNF, CXCL10, MCP1, and MIP1α (Huang et al. 2020; Yongzhi 2021), highlighting that critical COVID-19 might be implicated as a cytokine release syndrome (CRS), a disease developed through cytokine storm (Hirano and Murakami 2020; Mahmudpour et al. 2020; McGonagle et al. 2020; Yongzhi 2021).”
Background
Metadata
- Authors
- Mahmudpour, M., Roozbeh, J., Keshavarz, M., Farrokhi, S., & Nabipour, I.
- Affiliations
- Bushehr University of Medical Sciences (IR)
- Shiraz University of Medical Sciences (IR)
- Iranian Academy of Medical Sciences (IR)
- Corresponding author
- Nabipour, Iraj
- Venue
- Cytokine
- Publisher
- Elsevier BV
- Published
- 2020-09
- Volume
- 133
- Pages
- 155151
- ISSN
- 1043-4666 (ISSN-L)
- PMC
- PMC7260598
- OpenAlex
- W3030136428
- Cited by
- 461
- References
- 140
- Citations by year
- 2026: 8 · 2025: 18 · 2024: 47 · 2023: 61 · 2022: 104 · 2021: 168 · 2020: 52
- FWCI
- 4.55
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Cytokine (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Bushehr University of Medical Sciences
- Topics
- Health Sciences › Medicine › Infectious Diseases › COVID-19 Clinical Research Studies
- Health Sciences › Medicine › Infectious Diseases › SARS-CoV-2 and COVID-19 Research
- Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Renin-Angiotensin System Studies
- Keywords
- COVID-19 pandemic, cytokine storm, SARS-CoV-2, hyperinflammation, ACE2, renin-angiotensin-aldosterone system, Mas receptor, bradykinin B1 receptor, complement system, C5a, membrane attack complex, acute respiratory distress syndrome, intensive care unit patients, treatment options
- MeSH terms
- Betacoronavirus, Angiotensin-Converting Enzyme 2, COVID-19, SARS-CoV-2, Proto-Oncogene Mas, Bradykinin, Humans, Inflammation, Peptidyl-Dipeptidase A, Models, Molecular, Pneumonia, Viral, Proto-Oncogene Proteins, Renin-Angiotensin System, Complement C5a, Cytokines, Coronavirus Infections, Receptors, G-Protein-Coupled, Complement C5b, Pandemics, Spike Glycoprotein, Coronavirus
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