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.

Fig. 1

A systemic clinical manifestations of COVID-19. SARS-CoV-2 infects airway epithelial cells or immune cells via binding to ACE2 receptors, causing tissue damage and release of DAMPs, as well as production of inflammatory cytokines by epithelial cells and immune cells. Then, the crosstalk between epithelial cells and immune cells leads to a wide range of clinical manifestations, from mild forms (e.g., fever, cough, and myalgia); to moderate forms requiring hospitalization (pneumonia and localized inflammation); to severe/critical forms with a fatal outcome that are manifested as pneumonia, ARDS, DIC, CS, and multiorgan failure. DAMP danger-associated molecular pattern, ARDS acute respiratory distress syndrome, DIC disseminated intravascular coagulation

Fig. 2

The key immunopathology of severe COVID-19. The immunopathological manifestations of COVID-19 include lymphopenia, dysregulation of monocytes and macrophages, neutrophilia, ADE, reduced or delayed IFN-I response, and CS. Lymphopenia is commonly observed in severe COVID-19. In addition to decreased counts, lymphocytes often exhibit exhaustion phenotypes with the expression of higher levels of exhaustion markers PD-1, Tim-3, or NKG2A. Peripheral monocytes present a phenotype shift from CD16⁺ to CD14⁺, and BALF macrophages are increased with a blood-to-BALF transition course. Neutrophil counts are increased with the presence of neutrophil precursors in peripheral blood, especially in patients with severe COVID-19. The possible existence of ADE enhances the entry of SARS-CoV-2 into cells through interaction between Fc regions and Fc receptors, leading to the aggravation of COVID-19. A CS is characterized by highly elevated levels of pro-inflammatory mediators and is a particularly central feature for poor outcomes in patients with severe or critical infection. Reduced or delayed IFN-I response impedes viral clearance and induces paradoxical hyperinflammation, thus leading to the deterioration of prognosis in COVID-19 patients. BALF bronchoalveolar lavage fluid, ADE antibody-dependent enhancement

Fig. 3

The signaling pathways for the production and function of IFN-I after SARS-CoV-2 infection. After infection, the genomic ssRNAs and replicative dsRNA intermediates of SARS-CoV-2 are recognized by endosomal toll-like receptors TLR3, 7, 8, and cytosolic RNA sensors, RIG-1/MDA5; next, downstream transcription factors including NF-κB and IRF3/7 are activated to induce the production of pro-inflammatory cytokines and IFN-I. IFN-I can activate the JAK1/TYK2–STAT1/2 pathway, promoting the formation of the STAT1/2/IRF9 complex and initiating the transcription of ISGs to produce anti-virus mediators, and it can also nonconventionally activate inflammatory pathways such as NF-κB and MAPK pathways to induce the expression of pro-inflammatory cytokines and paradoxical hyperinflammation in COVID-19

Fig. 4

The immunopathological mechanisms of COVID-CS. SARS-CoV-2 infects the epithelial cells or immune cells, causing tissue damage and release of inflammatory cytokines (e.g., IL-1, IL-6, IL-12, and TNFα) by epithelial cells and immune cells. These inflammatory cytokines then recruit innate immune cells (monocytes, macrophages, neutrophils, DCs, and NK cells) and activate adaptive immune cells (CD4⁺ T cells and CD8⁺ T cells) to induce the occurrence of myelopoiesis and emergency granulopoiesis, as well as the production of sustained and excessive circulating cytokines that can further aggravate epithelial damage. In addition, overproduction of systemic cytokines triggers macrophage activation (i.e., MAS) and erythro-phagocytosis (i.e., HLH), resulting in anemia and gives rise to perturbation of vascular hemostasis, resulting in capillary leak syndrome, thrombosis, and DIC. These events together lead to ARDS, multiorgan failure, and death. HLH hemophagocytic lymphohistiocytosis, MAS macrophage activation syndrome, ARDS acute respiratory distress syndrome, DIC disseminated intravascular coagulation

Fig. 5

Inflammatory signaling cascades activated in COVID-CS. SARS-CoV-2 enters the host cells and is sensed by toll-like receptors (TLRs)3, 7, 8; RIG-I-like receptor, RIG-I or MDA5; and NOD-like receptor, NLRP3, that can also be directly activated by viral proteins or ROS released by apoptotic or inflamed cells. The downstream transcription factors IRF3/7 are activated to induce the production of IFN-I and related paradoxical hyperinflammation; NF-κB is activated to induce the production of pro-inflammatory cytokines; and NLRP3 inflammasome is activated to induce the production of mature IL-1β and IL-18. Pro-inflammatory cytokines such as IL-6, IL-2, TNF-α, and IFN-γ in turn activate the JAK-STAT or NF-κB signaling via binding to their receptors expressed on immune cells to induce more production of pro-inflammatory genes, forming a positive feedback to trigger the threshold of CS. Conversely, regulatory cytokines like IL-10 are compensatorily produced to antagonize immune hyperactivity

Fig. 6

The potential inhibitors and therapies to counteract COVID-CS. A variety of inhibitors or drugs have been applied or are under consideration to treat COVID-CS, including those targeting a single pro-inflammatory cytokine or its receptor and related signal pathway. In addition, several treatments such as intravenous immunoglobulin, corticosteroids, traditional Chinese medicine, and CDK7 inhibitor may have the potential to counteract multiple cytokines and pathways involved in COVID-CS. CDK7 cyclin-dependent kinase 7