Interleukin-6 Perpetrator of the COVID-19 Cytokine Storm

Abstract

COVID-19 has emerged as a global pandemic. It is mainly manifested as pneumonia which may deteriorate into severe respiratory failure. The major hallmark of the disease is the systemic inflammatory immune response characterized by Cytokine Storm (CS). CS is marked by elevated levels of inflammatory cytokines, mainly interleukin-6 (IL-6), IL-8, IL-10, tumour necrosis factor-α (TNF-α) and interferon-γ (IFN-γ). Of these, IL-6 is found to be significantly associated with higher mortality. IL-6 is also a robust marker for predicting disease prognosis and deterioration of clinical profile. In this review, the pivotal role played by IL-6 in the immuno-pathology of COVID-19 has been illustrated. The role of IL-6 as a pleiotropic cytokine executing both pro and anti-inflammatory activities has been reviewed. ADAM 10, a metalloproteinase switches the anti-inflammatory pathway of IL-6 to pro inflammatory hence blocking the action of ADAM 10 could be a new therapeutic strategy to mitigate the proinflammatory action of IL-6. Furthermore, we explore the role of anti-IL6 agents, IL-6 receptor antibodies which were being used for autoimmune diseases but now are being repurposed for the therapy of COVID-19.

Predictors of poor outcome in tocilizumab treated patients with Sars-CoV-2 related severe respiratory failure: A multicentre real world study

“…Blocking the cytokine cascade at different points, the dysregulation of inflammatory, immune and coagulation systems could be avoided and pulmonary damage limited reducing the risk of respiratory failure progression. Therefore it’s not surprising that research has focused on molecules aimed to avoid or estinguish the SARS-CoV2 related cytokine storm, such as Interleukin-1 (Anakinra) or IL-6 (Tocilizumab, Sarilumab) antagonists or JAK-STAT inhibitors (Baricitinib, Ruxolitinib) [6] . The IL-6 inhibitor Tocilizumab is a humanized monoclonal antibody which binds both with membrane bound and soluble receptors for IL-6 so blocking the signal transduction by which the JAK-STAT is activated perpetrating the cytokine storm [7] .…”

Hypoxic and Hyperoxic Breathing as a Complement to Low-Intensity Physical Exercise Programs: A Proof-of-Principle Study

“…In the presence of unregulated inflammatory response, proinflammatory and anti-inflammatory pathways are leading to a complex pattern of systemic activations consequent to cytokine storm, resulting in immune system impairment and proinflammatory imbalance. Downstream, the resulting "massive" inflammatory cascade, is responsible for global autonomic, endocrine, hematological, and immunological alterations, leading to a reversible or irreversible end-organ dysfunction and even death, as we have dramatically seen in the course of the current pandemic of severe acute respiratory syndrome corona virus 2 (SARS CoV-2) [6,7].…”

Role of Polypeptide Inflammatory Biomarkers in the Diagnosis and Monitoring of COVID-19

“…Upon interaction of SARS CoV-2 with the ACE-2 receptor, the S protein undergoes proteolytic activation via a two-step cleavage by host cell enzymes, one for priming at S1/S2 cleavage site and second for activation at a position adjacent to a fusion peptide within the S2 subunit. S protein is cleaved by cellular proteases including transmembrane serine protease 2 (TMPRSS2), cathepsin L and Furin, leading to viral entry through Clathrin facilitated endocytosis pathway (Yuki et al 2020 ; Attaway et al 2021 ; Shekhawat et al 2021 ). The spike fusion peptide produced by the action of Furin leads to cell fusion, resulting in viral spread and persistence.…”

“…It is a soluble protein whose expression is strictly under transcriptional and post transcriptional control. Its deregulated expression results in pathological effects hence it acts as a mediator of chronic inflammation and autoimmunity (Tanaka et al 2014 ; Shekhawat et al 2021 ). Normally, IL-6 is a pleiotropic protein that plays a role in inflammation, hematopoiesis and immune response.…”