The Role of Cytokines and Chemokines in Severe Acute Respiratory Syndrome Coronavirus 2 Infections

Abstract

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has resulted in countless infections and caused millions of deaths since its emergence in 2019. Coronavirus disease 2019 (COVID-19)-associated mortality is caused by uncontrolled inflammation, aberrant immune response, cytokine storm, and an imbalanced hyperactive immune system. The cytokine storm further results in multiple organ failure and lung immunopathology. Therefore, any potential treatments should focus on the direct elimination of viral particles, prevention strategies, and mitigation of the imbalanced (hyperactive) immune system. This review focuses on cytokine secretions of innate and adaptive immune responses against COVID-19, including interleukins, interferons, tumor necrosis factor-alpha, and other chemokines. In addition to the review focus, we discuss potential immunotherapeutic approaches based on relevant pathophysiological features, the systemic immune response against SARS-CoV-2, and data from recent clinical trials and experiments on the COVID-19-associated cytokine storm. Prompt use of these cytokines as diagnostic markers and aggressive prevention and management of the cytokine storm can help determine COVID-19-associated morbidity and mortality. The prophylaxis and rapid management of the cytokine storm appear to significantly improve disease outcomes. For these reasons, this study aims to provide advanced information to facilitate innovative strategies to survive in the COVID-19 pandemic.

Keywords: COVID-19; chemokines; cytokines; diagnostic markers; infection.

Figure 1

Cytokines and chemokines expression induced by SARS-CoV-2 in patients with COVID-19. (A) Epithelial cells have been shown to express TNF-α, IL-1, IL-6, and other chemokines (e.g., IL-8, CCL2, CCL7, CXCL10, G-CSF, and GM-CSF) as well as initiate immune responses following infection. (B) Innate immune cells, including dendritic cells, macrophages, circulating monocytes, neutrophils, and NK cells, are activated by SARS-CoV-2 infection to secrete various cytokines and chemokines to enhance both innate and adaptive immune cells. (C) Adaptive immune cells consisting of functional CD4⁺ T cells, Th1 cells, Th2 cells, Th17 cells, CD8⁺ T cells, and γδT cells defend against SARS-CoV-2 infection. The cytokines and chemokines expressed by adaptive immune cells interact in a positive feedback loop to strengthen innate immune responses. The cellular origin of each cytokine and its regulatory roles are shown in figure and Table 1. The persistent escalation of these responses leads to uncontrolled cytokine and chemokine expression, resulting in a life-threatening systemic inflammatory response syndrome, also known as “cytokine storm”. (D) Selected cytokine/chemokine modulation drugs that have been applied in COVID-19 clinical trials are shown in the upper right of the figure. They include neutralized antibodies (siltuximab, secukinumab, certolizumab); receptor antagonists (anakinra, sarilumab, tocilizumab), human recombinant proteins (IFN-β-1α, IFN-α-1β, IFN-α-2β); small-molecule drugs (baricitinib, remdesivir, molnupiravir, etanercept); and cell therapy (NKG2D-ACE2 CAR-NK cells). The drugs have been applied to COVID-19 patients to boost their immune systems and inhibit viral replication or cytokine storms. Figure created with BiorRender.com.

Figure 2

Multiple organ failure in SARS-CoV-2: pulmonary and extrapulmonary manifestations. Pulmonary manifestations: (A) Alveolar cells are infected by the angiotensin-converting enzyme 2 (ACE2) receptor. This leads to acute lung injury (ALI), activation of the renin-angiotensin system (RAS), and macrophage recruitment. Macrophages, activated by the ACE2-Ang II axis, can secrete IL-6, CCL2, VCAM-1, and E-selectin leading to endothelial dysfunction. Damaged endothelial cells may cause hyperfibrinolysis, activate coagulation, and increase inflammatory cytokine levels (IL-1 and TNF), which are strong inducers of hyaluronic acid-synthase-2 (HAS2) in CD31⁺ endothelium, EpCAM⁺ lung alveolar epithelial cells, and fibroblasts. The increased hyaluronic acid may cause bronchoconstriction. Extrapulmonary manifestations: (B) In neurons, elevated TNF-α and IL-6 secretions could increase the infiltration of immune cells and the permeability of the blood and cerebrospinal fluid barrier (BCSFB). CX3CL1 could also promote neurological vascular damage and thrombosis. IL-6 along with GM-CSF, IL-1β, TNF-α, CCL2, and CXCL10, could increase the severity of neurodegeneration, cognitive dysfunction, and stroke. (C) In the heart, infected cardiomyocytes would induce elevated secretions of IL-1, IL-6, TNF-α, and CCL2, damaging the myocardium and developing into hypoxia, respiratory distress, and even shock. (D) In the kidney, SARS-CoV-2 infects ACE2 expressing proximal tubules and the podocytes. The infected podocytes promote an imbalanced RAS, which leads to acute kidney injury (AKI). Moreover, IL-6, IL-1β, IL-10, GM-CSF, IFNs, CXCL10, CCL2 and TNF-α promote AKI persistence. (E) In the liver, infected hepatocytes trigger elevated serum IL-1, IL-2, IL-6, IL-10, and IFNγ, as well as pathogenic cytokine secretions mediated by T cells (GM-CSF, IL-6, and IFN-γ). The immune-mediated injury would lead to liver dysfunction and systemic inflammatory response syndrome (SIRS). Figure created with BioRender.com.