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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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In the citing paper
“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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“The proposed study is a proof-of-principle that the release of key proteins of the COVID-19 “cytokine storm” [16,18] can be strongly inhibited by mimicking the biological activity of microRNAs regulating the respective mRNAs.”
Neuroimmune multi-hit perspective of coronaviral infection
Hayley, S. P., & Sun, H. (2021) · Journal of Neuroinflammation · doi:10.1186/s12974-021-02282-0 · Cited by 21
“It was further suggested that activated complement elements can damage sensitive CNS cells, following their activation either peripherally or within the confines of cerebroventricular system [78].”
Multimodality Imaging for Cardiac Evaluation in Patients with COVID-19
Goerlich, E., Minhas, A., Mukherjee, M., Sheikh, F. H., Gilotra, N. A., Sharma, G. V., Michos, E. D., & Hays, A. G. (2021) · Current Cardiology Reports · doi:10.1007/s11886-021-01483-6 · Cited by 20
Nazerian, Y., Vakili, K. G., Ebrahimi, A., & Niknejad, H. (2021) · Frontiers in Cell and Developmental Biology · doi:10.3389/fcell.2021.717587 · Cited by 22
MiR-26a Reduces Inflammatory Responses via Inhibition of PGE2 Production by Targeting COX-2
Yu, T., Wang, P., Wu, Y., Zhong, J., Chen, Q.-S., Wang, D.-M., Chen, H., Hu, S.-F., & Wu, Q. (2022) · Inflammation · doi:10.1007/s10753-022-01631-2 · Cited by 21
“” On the one hand, it can help the human body to resist pathogen infection and restore tissue structure and physiological function [1, 2]; on the other hand, uncontrolled inflammation can cause tissue damage and host diseases, such as septic shock [3], organ failure [4], cardiovascular diseases [5], and cancer [6]; ev…”
BackgroundShojaei, M., Foshati, S., Abdi, M., Askari, G., Sukhorukov, V. N., Bagherniya, M., & Sahebkar, A. (2023) · Phytotherapy Research · doi:10.1002/ptr.7778 · Cited by 20
“It has been indicated that SARS-CoV-2 directly activates NF-κB through toll-like receptors (TLRs) and renin-angiotensin-aldosterone system (RAAS) system components (Mahmudpour et al., 2020; Rattis et al., 2021b).”
BackgroundDas, A., & Rana, S. (2021) · Computational Biology and Chemistry · doi:10.1016/j.compbiolchem.2021.107482 · Cited by 20
Neuropsychiatric Disorders and COVID-19: What We Know So Far
Majolo, F., da Silva, G. L., Vieira, L., Anli, C., Timmers, L. F. S. M., Laufer, S., & Goettert, M. I. (2021) · Pharmaceuticals · doi:10.3390/ph14090933 · Cited by 22
Presentation and Management of Cutaneous Manifestations of COVID-19
Almeida, G., Arruda, S., Marques, E., Michalany, N., & Sadick, N. S. (2020) · Journal of Drugs in Dermatology · doi:10.36849/jdd.5676 · Cited by 19
Nervous System Involvement in COVID-19: a Review of the Current Knowledge
Norouzi, M., Miar, P., Norouzi, S., & Nikpour, P. (2021) · Molecular Neurobiology · doi:10.1007/s12035-021-02347-4 · Cited by 19
Tamayo-Velasco, Á., Ponce, M. J. P., Álvarez, F. J., Gonzalo‐Benito, H., de la Fuente, I., González, S. P., Rico, L., García, M. T. J., Rodríguez, A. S., Villaizan, M. H., et al. (2021) · Frontiers in Immunology · doi:10.3389/fimmu.2021.726283 · Cited by 20
Peddapalli, A., Gehani, M., Kalle, A. M., Peddapalli, S. R., Peter, A. E., & Sharad, S. (2021) · Viruses · doi:10.3390/v13030378 · Cited by 19
Recent clinical findings on the role of kinase inhibitors in COVID-19 management
Malekinejad, Z., Baghbanzadeh, A., Nakhlband, A., Baradaran, B., Jafari, S., Bagheri, Y., Raei, F., Montazersaheb, S., & Farahzadi, R. (2022) · Life Sciences · doi:10.1016/j.lfs.2022.120809 · Cited by 20
Tapela, K., Oyawoye, F. O., Olwal, C. O., Opurum, P. C., Amponsah, J. A., Segbedzi, K. A. L., Tetteh, B. E., Kumi-Ansah, F., Mutungi, J. K., Obodai, E., et al. (2022) · BMC Medicine · doi:10.1186/s12916-022-02571-2 · Cited by 18
AI-CoV Study: Autoimmune Encephalitis Associated With COVID-19 and Its Vaccines—A Systematic Review
Samim, M. M., Dhar, D., Goyal, S., Dey, T., Parvin, N., Shah, R., Singh, V., Chowdhury, S., Lal, B. M., Varghese, N., et al. (2022) · Journal of Clinical Neurology · doi:10.3988/jcn.2022.18.6.692 · Cited by 19
An update on host immunity correlates and prospects of re-infection in COVID-19
Negi, N., Maurya, S. P., Singh, R., & Das, B. K. (2021) · International Reviews of Immunology · doi:10.1080/08830185.2021.2019727 · Cited by 20
Meta-Analysis of APP Expression Modulated by SARS-CoV-2 Infection via the ACE2 Receptor
Caradonna, A., Patel, T. R., Toleska, M., Alabed, S. T., & Chang, S. L. (2022) · International Journal of Molecular Sciences · doi:10.3390/ijms23031182 · Cited by 18
Impact of COVID-19 on the Intestinal Microbiome
Venegas-Borsellino, C. P., Sankararaman, S., Roche, K. F., Burns, J., & Landis, R. M. (2021) · Current Nutrition Reports · doi:10.1007/s13668-021-00375-z · Cited by 17
Elderberries as a potential supplement to improve vascular function in a SARS‐CoV ‐2 environment
Festa, J., Singh, H., Hussain, A., & Boit, M. D. (2022) · Journal of Food Biochemistry · doi:10.1111/jfbc.14091 · Cited by 17
Hearing screening test in neonates born to COVID-19–positive mothers
Goulioumis, A. K., Angelopoulou, M., Kourelis, K. G., Mourtzouchos, K., Tsiakou, M., & Asimakopoulos, A. (2022) · European Journal of Pediatrics · doi:10.1007/s00431-022-04770-8 · Cited by 17
“This cytokine storm can subsequently activate the complement subunits C3a and C5a resulting in decreased differentiation of T regulatory cells (Treg) and increased differentiation of T helper 17 (Th17) that ultimately conclude in an uncontrolled inflammatory response that can have a detrimental impact on central and p…”
BackgroundEffects of PM2.5 Exposure on the ACE/ACE2 Pathway: Possible Implication in COVID-19 Pandemic
Botto, L., Lonati, E., Russo, S., Cazzaniga, E., Bulbarelli, A., & Palestini, P. (2023) · International Journal of Environmental Research and Public Health · doi:10.3390/ijerph20054393 · Cited by 18
“The loss of the modulatory effect of Ang(1–7), obtained by its binding to the Mas receptor that attenuates inflammatory response, may be a further contributing factor in the hyper-inflammation status of severe cases of COVID-19 [31].”
BackgroundPhytotherapics in COVID19 : Why palmitoylethanolamide?
Pesce, M., Seguella, L., Cassarano, S., Aurino, L., Sanseverino, W., Lu, J., Corpetti, C., Re, A., Vincenzi, M., Sarnelli, G., et al. (2020) · Phytotherapy Research · doi:10.1002/ptr.6978 · Cited by 18
Metabolomic profiling of threeAraucariaspecies, and their possible potential role against COVID-19
El‐Hawary, S. S., Rabeh, M. A., Raey, M. A. E., El-Kader, E. M. A., Sobeh, M., Abdelmohsen, U. R., Albohy, A., Andrianov, A. M., Bosko, I. P., Al-Sanea, M. M., et al. (2021) · Journal of Biomolecular Structure and Dynamics · doi:10.1080/07391102.2021.1885494 · Cited by 17
Effect of Pirfenidone on Risk of Pulmonary Fibrosis in COVID-19 Patients Experiencing Cytokine Storm
Boshra, M. S., Warda, A. E. A., Sayed, M. A., Elkomy, M. H., Alotaibi, N. H., Mohsen, M., & Sarhan, R. M. (2022) · Healthcare · doi:10.3390/healthcare10122387 · Cited by 17
Balasubramanian, N., James, T. D., Selvakumar, G. P., Reinhardt, J., & Marcinkiewcz, C. A. (2022) · Alcoholism Clinical and Experimental Research · doi:10.1111/acer.15000 · Cited by 17
Mishra, R., Behera, L. M., & Rana, S. (2020) · Journal of Biomolecular Structure and Dynamics · doi:10.1080/07391102.2020.1820381 · Cited by 17
“The hyperinflammatory signal produced by the ‘cytokine storm’ (Hu et al., 2020; Mahmudpour et al., 2020; Mehta et al., 2020; Ye et al., 2020) is the prime contributor in the pathogenesis of many immunological and non-immunological diseases, including the current pandemic faced by the world in the name of COVID19 (Cevi…”
BackgroundLocalized delivery of nanomedicine and antibodies for combating COVID-19
Tu, B., Gao, Y., An, X., Wang, H., & Huang, Y. (2022) · Acta Pharmaceutica Sinica B · doi:10.1016/j.apsb.2022.09.011 · Cited by 16
Milton‐Laskibar, I., Trepiana, J., Macarulla, M. T., Gómez‐Zorita, S., Arellano-García, L., Fernández‐Quintela, A., & Portillo, M. P. (2022) · Journal of Physiology and Biochemistry · doi:10.1007/s13105-022-00926-0 · Cited by 16
“Recently, elevated Ang II levels in plasma in COVID-19 patients with lung injury have been reported [46].”
BackgroundChangsan, N., Sawatdee, S., Suedee, R., Chunhachaichana, C., & Srichana, T. (2023) · International Journal of Pharmaceutics · doi:10.1016/j.ijpharm.2023.123035 · Cited by 16
“These immune reactions might 600 indicate the onset of a cytokine storm with severe clinicopathological consequences and severe 601 COVID-19 disease (Mahmudpour et al., 2020).”
Immunomodulating Phytochemicals: An Insight into their Potential Use in Cytokine Storm Situations.
Alarabei, A. A., Aziz, N. A. L. A., Razak, N. I. A., Abas, R., Bahari, H., Abdullah, M. A., Hussain, M. K., Majid, A. M. S. A., & Basir, R. (2023) · Advanced Pharmaceutical Bulletin · doi:10.34172/apb.2024.001 · Cited by 25
“34 Relevant keywords were employed in searching multiple data sources which included PubMed, SpringerLink, ScienceDirect, Google Scholar, and Scopus.”
MethodPerspectives and Challenges in the Fight Against COVID-19: The Role of Genetic Variability
Guilger‐Casagrande, M., de Barros, C. T., Antunes, V. A. N., de Araújo, D. R., & de Lima, R. (2021) · Frontiers in Cellular and Infection Microbiology · doi:10.3389/fcimb.2021.598875 · Cited by 17
“Moreover, the renin–angiotensin–aldosterone system imbalance evokes pronounced detrimental effects in all COVID-19 stages, since multiple organ failure and a hyperinflammatory response are the main clinical findings in severe cases (Mahmudpour et al., 2020).”
BackgroundInfluentialKaur, G., Yogeswaran, S., Muthumalage, T., & Rahman, I. (2021) · Frontiers in Physiology · doi:10.3389/fphys.2021.653045 · Cited by 17
Khodabakhsh, P., Taei, A. A., Mohseni, M., Zanjanbar, D. B., Khalili, H., Masoumi, K., Shirazi, A. H. A., & Dargahi, L. (2021) · Archives of Medical Research · doi:10.1016/j.arcmed.2021.05.007 · Cited by 15
Fan, Y., Wang, Y., Yu, S., Chang, J. B. P., Yan, Y., Wang, Y., & Bian, Y. (2021) · Chinese Medicine · doi:10.1186/s13020-021-00478-3 · Cited by 15
“When the S protein of SARS-CoV-2 attaches to ACE2, its intracellular binding site down-regulates ACE2, which may cause the cytokine storm through dysregulation of ACE/angiotensin II/AT1R axis, attenuation of ACE2/MasR axis and increased activation of ACE2/bradykinin B1R/DABK axis [41].”
BackgroundGholizadeh, M., Saeedy, S. A. G., Abdi, A., Khademi, F., Lorian, K., Clark, C. C. T., & Djafarian, K. (2021) · Clinical Nutrition Open Science · doi:10.1016/j.nutos.2021.09.003 · Cited by 15
“Regarding the possibility of the development of cytokine storm syndrome in the course of the COVID-19 [41,42], and the bene fi cial effects of vitamin C on the alleviation of in fl ammation in cytokine storm syndrome [43 e 45], the results of this study could be extrapolated to COVID-19 patients.”
ResultSkeletal Muscle and COVID-19: The Potential Involvement of Bioactive Sphingolipids
Meacci, E., Pierucci, F., & Garcia‐Gil, M. (2022) · Biomedicines · doi:10.3390/biomedicines10051068 · Cited by 17
SARS-CoV-2-mediated liver injury: pathophysiology and mechanisms of disease
Choaib, A., Issa, E., Choueiry, F. E., Eldin, J. N., Shbaklo, K., Alhajj, M., Sawaya, R. T., Assi, G., Nader, M., Chatila, R., et al. (2022) · Inflammation Research · doi:10.1007/s00011-022-01683-y · Cited by 15
“1 3 terminal complement variable C5b-9 stimulates the release of IL-6 from vascular smooth muscle cells by stimulating the redox-sensitive transcription factor NF-κB, activator protein 1 (AP-1), and MCP-1 [116].”
BackgroundMalchair, P., Giol, J., García, V. G., Rodrı́guez, O., Ruibal, J. C., Pellejero, A. Z., Llopis, F., Matellán, L., Bernal, T., Solís, B., et al. (2023) · Clinical Infectious Diseases · doi:10.1093/cid/ciac984 · Cited by 15
“SARS-CoV-2–driven angiotensin-converting enzyme 2 dysfunction can evolve into a hyperinflammatory status through an array of intertwined pathways [11, 26].”
BackgroundHan, L., Wu, X., Wang, O., Luan, X., Velander, W. H., Aynardi, M. C., Halstead, E. S., Bonavia, A. S., Jin, R., Li, G., et al. (2023) · Theranostics · doi:10.7150/thno.83942 · Cited by 14
“Hyperinflammation can rapidly progress to disseminated intravascular coagulation, vascular leakage, acute respiratory distress syndrome (ARDS), multi-organ dysfunction (MODS), and death [6,7].”
Islam, F., Habib, S., Badruddza, K., Rahman, M., Islam, M. R., Sultana, S., & Nessa, A. (2024) · Cureus · doi:10.7759/cureus.57610 · Cited by 17
“Higher concentrations of IL-2, IL-6, IL-8, and TNF-α were also reported in ICU patients with COVID-19 in comparison to non-ICU patients [22].”
ResultSharma, A. K., Shah, M. A., Lakshmi, S., Sane, H. M., Captain, J., Gokulchandran, N., Khubchandani, P., Pradeep, M., Gote, P., Tuppekar, B. G., et al. (2021) · International Immunopharmacology · doi:10.1016/j.intimp.2021.107743 · Cited by 15
Gjurašin, B., Santini, M., Krajinović, V., Papić, N., Atelj, A., Kotarski, V., Krznarić, J., Vargović, M., & Kutleša, M. (2020) · Wiener klinische Wochenschrift · doi:10.1007/s00508-020-01759-x · Cited by 15
Moatăr, A. I., Chiş, A. R., Marian, C., & Sîrbu, I. O. (2022) · International Journal of Molecular Sciences · doi:10.3390/ijms23169239 · Cited by 14
COVID-19 and hepatic injury: Diversity and risk assessment
Ali, F. E. M., El‐Aziz, M. K. A., Ali, M. M., Ghogar, O. M., & Bakr, A. G. (2023) · World Journal of Gastroenterology · doi:10.3748/wjg.v29.i3.425 · Cited by 14
Yang, G., Zhang, S., Song, W., Bai, X., Li, L., Luo, F., Cheng, Y., Wang, D., Wang, Y., Chen, J., et al. (2023) · Small · doi:10.1002/smll.202207066 · Cited by 14
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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