IL-6: Relevance for immunopathology of SARS-CoV-2

Abstract

COVID-19 mortality is strongly associated with the development of severe pneumonia and acute respiratory distress syndrome with the worst outcome resulting in cytokine release syndrome and multiorgan failure. It is becoming critically important to identify at the early stage of the infection those patients who are prone to develop the most adverse effects. Elevated systemic interleukin-6 levels in patients with COVID-19 are considered as a relevant parameter in predicting most severe course of disease and the need for intensive care. This review discusses the mechanisms by which IL-6 may possibly contribute to disease exacerbation and the potential of therapeutic approaches based on anti-IL-6 biologics.

Keywords: Anti-cytokine therapeutics; Cytokine release syndrome; IL-6; SARS-CoV-2.

Fig. 1

Schematic representation of SARS-CoV-2 interaction with a target cell. Binding of virion to ACE2 is followed by serine protease, TMPRSS2, cleavage of the viral spike protein and induction of internalization of the complex with subsequent reduction of ACE2 surface availability. Then another protease, Furin, releases spike fusion peptide, and the virus enters the host cell through an endosomal pathway.

Fig. 2

Role of IL-6 in respiratory viral infections. IL-6 demonstrates opposing effects during the immune response to viral infections in the lungs. IL-6 promotes highly specific reaction of adaptive immunity by stimulating of CD8⁺ T cells and B cells, which is balanced by T regulatory cells. Also, IL-6 facilitates survival of phagocytic neutrophils. On the other hand, IL-6 can provide unfavorable Th2 and Th17 over Th1 helper differentiation and facilitate tissue injury by dysregulation of extracellular matrix and attraction of neutrophils and pro-inflammatory macrophages.

Fig. 3

Cytokine release syndrome in COVID-19. SARS-CoV-2 replicates in alveolar epithelial cells. After the virions are released, they can infect or are being captured by macrophages, dendritic cells and neutrophils. At the same time, damaged epithelial cells produce alarmins, which are sensed by the neighboring epithelial and myeloid cells. All these events lead to release of proinflammatory cytokines, increase of alveolar vessel permeability and cell recruitment to the site of infection, forming positive loop for pathological activation of IL-6, IL-1, TNF and other proinflammatory cytokines. Due to high permeability of pulmonary vessels under inflammatory conditions, SARS-CoV-2 can inseminate distant ACE2-expressing tissues (intestine, kidney, pancreas), and trigger burst of inflammation at distant sites.

Fig. 4

ACE2 downregulation may drive IL-6 production in Angiotensin II-dependent manner. A – in healthy state pro-inflammatory signaling of Angiotensin II via Angiotensin 1 receptor (AT1R) is stabilized by Angiotensin 1–7 (ACE2-Angiotensin I proteolysis product) signaling via Mas receptor (MasR) that has anti-inflammatory effect. B – virus-mediated down-regulation of ACE2 leads to Angiotensin II accumulation in the absence of Angiotensin 1–7 and acceleration of its proinflammatory effect. AT1R downstream activation of NADPH oxidase results in elevated ROS directly promoting IL-6 expression. In its turn, IL-6 can positively regulate AT1R levels. Thus, by acting together these processes exacerbate hypertension, edema, infiltration of immune cells and inflammation in COVID-19 affected lungs.