Cytokines and Chemokines in SARS-CoV-2 Infections—Therapeutic Strategies Targeting Cytokine Storm

Pum, Alexandra; Ennemoser, Maria; Adage, Tiziana; Kungl, Andreas J.

doi:10.3390/biom11010091

Cited by 71 publications

(68 citation statements)

References 117 publications

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“…A network of cytokines and chemokines has been implicated in cytokine storm development in several recent studies. Furthermore, an array of chemokines, including CCL2, CCL3, CCL4, CCL7, CXCL1, CXCL3, CXCL8, and CXCL10, have been reported as critical players in the initiation and progression of the cytokine storm [ 44 , 45 , 46 , 47 ]. The analysis of bronchoalveolar lavage fluid (BALF) from severely ill patients with SARS-CoV-2 infection recently indicated that chemokines play a significant role in disease prognosis.…”

Section: Cytokinesand Chemokines Associated With Cytokine Stormmentioning

confidence: 99%

“…Furthermore, recent lung autopsy findings have suggested that seriously ill patients with COVID-19 have considerably higher levels of a set of chemokines, including CCL2, CXCL5, and CXCL6, than moderately ill patients [53]. As a result, several studies that corroborate each other strongly proposed that chemokines are crucially implicated in the poor prognosis, which results in a higher fatality rate [44,45,[53][54][55].…”

Section: Cytokinesand Chemokines Associated With Cytokine Stormmentioning

confidence: 99%

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Role of Inflammatory Cytokines in COVID-19 Patients: A Review on Molecular Mechanisms, Immune Functions, Immunopathology and Immunomodulatory Drugs to Counter Cytokine Storm

et al. 2021

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Coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is a severe pandemic of the current century. The vicious tentacles of the disease have been disseminated worldwide with unknown complications and repercussions. Advanced COVID-19 syndrome is characterized by the uncontrolled and elevated release of pro-inflammatory cytokines and suppressed immunity, leading to the cytokine storm. The uncontrolled and dysregulated secretion of inflammatory and pro-inflammatory cytokines is positively associated with the severity of the viral infection and mortality rate. The secretion of various pro-inflammatory cytokines such as TNF-α, IL-1, and IL-6 leads to a hyperinflammatory response by recruiting macrophages, T and B cells in the lung alveolar cells. Moreover, it has been hypothesized that immune cells such as macrophages recruit inflammatory monocytes in the alveolar cells and allow the production of large amounts of cytokines in the alveoli, leading to a hyperinflammatory response in severely ill patients with COVID-19. This cascade of events may lead to multiple organ failure, acute respiratory distress, or pneumonia. Although the disease has a higher survival rate than other chronic diseases, the incidence of complications in the geriatric population are considerably high, with more systemic complications. This review sheds light on the pivotal roles played by various inflammatory markers in COVID-19-related complications. Different molecular pathways, such as the activation of JAK and JAK/STAT signaling are crucial in the progression of cytokine storm; hence, various mechanisms, immunological pathways, and functions of cytokines and other inflammatory markers have been discussed. A thorough understanding of cytokines’ molecular pathways and their activation procedures will add more insight into understanding immunopathology and designing appropriate drugs, therapies, and control measures to counter COVID-19. Recently, anti-inflammatory drugs and several antiviral drugs have been reported as effective therapeutic drug candidates to control hypercytokinemia or cytokine storm. Hence, the present review also discussed prospective anti-inflammatory and relevant immunomodulatory drugs currently in various trial phases and their possible implications.

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Section: Cytokinesand Chemokines Associated With Cytokine Stormmentioning

confidence: 99%

Section: Cytokinesand Chemokines Associated With Cytokine Stormmentioning

confidence: 99%

Role of Inflammatory Cytokines in COVID-19 Patients: A Review on Molecular Mechanisms, Immune Functions, Immunopathology and Immunomodulatory Drugs to Counter Cytokine Storm

et al. 2021

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“…Immune hyperreactivity or a failure to resolve the inflammatory reaction due to immune dysregulation in the lungs leads in severely ill patients to excessive production of cytokines/chemokines causing a cytokine storm characterized by elevated levels of circulating cytokines, systemic inflammatory symptoms and multiorgan dysfunction [76] , [77] , [78] . Inflammatory cytokines and chemokines that are elevated in the circulation of patients with COVID-19 include interleukin-1β (IL-1 β), IL-6, TNF, IFN-γ, MCP1 (CCL2), MIP1α (CCL3), MIP1β (CCL4), angiopoietin 2, and vascular endothelial growth factor (VEGF) 79 . The cytokine storm is accompanied by aberrant activation of circulating monocytes, increase in neutrophils, and marked decrease in circulating T and B lymphocytes 27 , 78 .…”

Section: Mechanisms Of Endothelial Injury and Thrombosis In The Vasculature Of Peripheral Organsmentioning

confidence: 99%

COVID-19 Vasculopathy: Mounting Evidence for an Indirect Mechanism of Endothelial Injury

Nicosia

Ligresti

Caporarello

et al. 2021

The American Journal of Pathology

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COVID-19 patients who are critically ill develop vascular complications characterized by thrombosis of small, medium and large vessels. Dysfunction of the vascular endothelium due to the SARS-CoV-2 infection has been implicated in the pathogenesis of the COVID-19 vasculopathy. Although initial reports suggested that endothelial injury was caused directly by the virus, recent studies indicate that endothelial cells do not express ACE2 – the receptor that SARS-CoV-2 uses to gain entry into cells – or express it at low levels and are resistant to the infection. These new findings, together with the observation that COVID-19 triggers a cytokine storm capable of injuring the endothelium and disrupting its antithrombogenic properties, favor an indirect mechanism of endothelial injury mediated, locally, by an augmented inflammatory reaction to infected nonendothelial cells such as the bronchial and alveolar epithelium and, systemically, by the excessive immune response to infection. Here we review the vascular pathology of COVID-19 and critically discuss the potential mechanisms of endothelial injury in this disease.

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“…Besides the cytokines, several other small chemical molecules or chemokines such as CCL2 (MCP1), CCL3 (MIP1α), CXCL10 (IP-10) have been reported to be higher in the serum of severely ill patients with COVID-19 [ 73 , 74 , 75 , 76 ]. These chemokines may correlate with the increased level of cytokines as they act as chemoattractants for several immune cells and lead to the cytokine storm via modulating the immune response in severe cases [ 75 , 76 , 77 , 78 , 79 ]. For example, Chi et al detected the production of pro-inflammatory chemokines and cytokines in the serum samples of asymptomatic as well as symptomatic patients [ 80 ].…”

Section: Factors Influencing Inflammatory Cytokine Production By Modulation Of the Immune Systemmentioning

confidence: 99%

“…The early generation of IL-1RA and IL-10 were found to be correlated with the severity of the disease. The level of most cytokines, including IFN-γ and IL-6, was increased in the later phases of the disease, whereas TNF-α and GM-CSF presented no meaningful differences between mild and severe cases [ 76 , 77 , 83 ]. Furthermore, NLRP3 inflammasome releases proinflammatory cytokines (IL-1β, IL-18) and triggers gasdermin D-mediated pyroptotic cell death, as a result of which elevated level of enzyme lactate dehydrogenase (LDH) is observed in the blood of patients with COVID-19 and correlated with disease severity [ 78 , 84 , 85 , 86 ].…”

Section: Factors Influencing Inflammatory Cytokine Production By Modulation Of the Immune Systemmentioning

confidence: 99%

Diverse Immunological Factors Influencing Pathogenesis in Patients with COVID-19: A Review on Viral Dissemination, Immunotherapeutic Options to Counter Cytokine Storm and Inflammatory Responses

et al. 2021

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The pathogenesis of coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is still not fully unraveled. Though preventive vaccines and treatment methods are out on the market, a specific cure for the disease has not been discovered. Recent investigations and research studies primarily focus on the immunopathology of the disease. A healthy immune system responds immediately after viral entry, causing immediate viral annihilation and recovery. However, an impaired immune system causes extensive systemic damage due to an unregulated immune response characterized by the hypersecretion of chemokines and cytokines. The elevated levels of cytokine or hypercytokinemia leads to acute respiratory distress syndrome (ARDS) along with multiple organ damage. Moreover, the immune response against SARS-CoV-2 has been linked with race, gender, and age; hence, this viral infection’s outcome differs among the patients. Many therapeutic strategies focusing on immunomodulation have been tested out to assuage the cytokine storm in patients with severe COVID-19. A thorough understanding of the diverse signaling pathways triggered by the SARS-CoV-2 virus is essential before contemplating relief measures. This present review explains the interrelationships of hyperinflammatory response or cytokine storm with organ damage and the disease severity. Furthermore, we have thrown light on the diverse mechanisms and risk factors that influence pathogenesis and the molecular pathways that lead to severe SARS-CoV-2 infection and multiple organ damage. Recognition of altered pathways of a dysregulated immune system can be a loophole to identify potential target markers. Identifying biomarkers in the dysregulated pathway can aid in better clinical management for patients with severe COVID-19 disease. A special focus has also been given to potent inhibitors of proinflammatory cytokines, immunomodulatory and immunotherapeutic options to ameliorate cytokine storm and inflammatory responses in patients affected with COVID-19.

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Cytokines and Chemokines in SARS-CoV-2 Infections—Therapeutic Strategies Targeting Cytokine Storm

Cited by 71 publications

References 117 publications

Role of Inflammatory Cytokines in COVID-19 Patients: A Review on Molecular Mechanisms, Immune Functions, Immunopathology and Immunomodulatory Drugs to Counter Cytokine Storm

Role of Inflammatory Cytokines in COVID-19 Patients: A Review on Molecular Mechanisms, Immune Functions, Immunopathology and Immunomodulatory Drugs to Counter Cytokine Storm

COVID-19 Vasculopathy: Mounting Evidence for an Indirect Mechanism of Endothelial Injury

Diverse Immunological Factors Influencing Pathogenesis in Patients with COVID-19: A Review on Viral Dissemination, Immunotherapeutic Options to Counter Cytokine Storm and Inflammatory Responses

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