The signal pathways and treatment of cytokine storm in COVID-19

Abstract

The Coronavirus Disease 2019 (COVID-19) pandemic has become a global crisis and is more devastating than any other previous infectious disease. It has affected a significant proportion of the global population both physically and mentally, and destroyed businesses and societies. Current evidence suggested that immunopathology may be responsible for COVID-19 pathogenesis, including lymphopenia, neutrophilia, dysregulation of monocytes and macrophages, reduced or delayed type I interferon (IFN-I) response, antibody-dependent enhancement, and especially, cytokine storm (CS). The CS is characterized by hyperproduction of an array of pro-inflammatory cytokines and is closely associated with poor prognosis. These excessively secreted pro-inflammatory cytokines initiate different inflammatory signaling pathways via their receptors on immune and tissue cells, resulting in complicated medical symptoms including fever, capillary leak syndrome, disseminated intravascular coagulation, acute respiratory distress syndrome, and multiorgan failure, ultimately leading to death in the most severe cases. Therefore, it is clinically important to understand the initiation and signaling pathways of CS to develop more effective treatment strategies for COVID-19. Herein, we discuss the latest developments in the immunopathological characteristics of COVID-19 and focus on CS including the current research status of the different cytokines involved. We also discuss the induction, function, downstream signaling, and existing and potential interventions for targeting these cytokines or related signal pathways. We believe that a comprehensive understanding of CS in COVID-19 will help to develop better strategies to effectively control immunopathology in this disease and other infectious and inflammatory diseases.

The Immunology of SARS-CoV-2 Infection and Vaccines in Solid Organ Transplant Recipients

“…Cytokine storm, hyperinflammation, multiorgan failure, and acute respiratory distress syndrome were described in COVID-19 patients with high fever, dyspnea, lymphopenia, and high serum ferritin, D-dimers, C-reactive protein (CRP), and cytokines, including IL-1b, IL-6, and TNF-α [ 31 , 32 ]. Several studies showed that the severity of COVID-19 symptoms positively correlated with blood levels of proinflammatory cytokines and chemokines (e.g., IL-1b, TNF-α, monocyte chemoattractant protein 1 [MCP-1], MCP-3, cytosolic carboxypeptidase 2 [CCL2], CCL3, IL-2, sIL-2RA, IL-6, IL-7, IL-17, IL-18, granulocyte colony-stimulating factor [G-CSF], interferon gamma-induced protein 10 [IP10], macrophage colony-stimulating factor [M-CSF], and microprotein 1a [MIP-1a]) and anti-inflammatory cytokines (e.g., IL-10) [ 33 , 34 , 35 , 36 , 37 , 38 ].…”

Coagulopathies after Vaccination against SARS-CoV-2 May Be Derived from a Combined Effect of SARS-CoV-2 Spike Protein and Adenovirus Vector-Triggered Signaling Pathways

“…Various other cytokines, such as G-SCF or GM-CSF, and a variety of chemokines such as IL-8, MCP-1, MIP1α, and MIP1β found to be elevated in acute COVID-19 patients [ 18 ] are also known to activate the JAK/SAT3 pathway [ 88 , 92 ]. The enhanced transcription of JAK/STAT3 activators, such as IL-6 and multiple chemokines (including IL-8, MCP-1, MIP1α, and MIP1β), found during acute respiratory viral infections, including also SARS-CoV-2, is largely triggered also by NF-κB pathway activation [ 38 , 93 , 94 ].…”

An overview on tumor treating fields (TTFields) technology as a new potential subsidiary biophysical treatment for COVID-19

“…Thus, targeting macrophages is suggested as a therapeutic option for COVID-19 infection [ 135 ]. Hence, using anti-inflammatory pharmaceuticals along with applying TTFields can be a solution for this challenge [ 136 – 138 ]. However, the role of macrophages in COVID-19 is a controversial area [ 139 , 140 ].…”