Macrophage responses associated with COVID-19: A pharmacological perspective

Abstract

COVID-19 has caused worldwide death and economic destruction. The pandemic is the result of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), which has demonstrated high rates of infectivity leading to great morbidity and mortality in vulnerable populations. At present, scientists are exploring various approaches to curb this pandemic and alleviate its health consequences, while racing to develop a vaccine. A particularly insidious aspect of COVID-19 is the delayed overactivation of the body's immune system that is manifested as the cytokine storm. This unbridled production of pro-inflammatory cytokines and chemokines can directly or indirectly cause massive organ damage and failure. Systemic vascular endothelial inflammation and thrombocytopenia are potential consequences as well. In the case of COVID-19, the cytokine storm often fits the pattern of the macrophage activation syndrome with lymphocytopenia. The basis for the imbalance between the innate and adaptive immune systems is not clearly defined, but highlights the effect of SARS-CoV-2 on macrophages. Here we discuss the potential underlying basis for the impact of SARS-CoV-2 on macrophages, both direct and indirect, and potential therapeutic targets. These include granulocyte-macrophage colony-stimulating factor (GM-CSF), interleukin 6 (IL-6), interferons, and CXCL10 (IP-10). Various biopharmaceuticals are being repurposed to target the cytokine storm in COVID-19 patients. In addition, we discuss the rationale for activating the macrophage alpha 7 nicotinic receptors as a therapeutic target. A better understanding of the molecular consequences of SARS-CoV-2 infection of macrophages could lead to novel and more effective treatments for COVID-19.

Keywords: Biologicals; Cytokine storm; Immunomodulation therapy; Immunopharmacology; Macrophage activation syndrome; Pandemic.

Fig. 1

– Macrophages at the center of the cytokine storm. With inflammation, macrophages, T cells, endothelial cells and a number of other immune and mesenchymal cells, produce the monomeric glycoprotein granulocyte-macrophage colony-stimulating factor (GM-CSF) (red arrows). Besides stimulating the production of granulocytes and monocytes, GM-CSF can serve as a chemoattractant for the migration of monocytes and neutrophils into the tissue (blue arrows), and can alter neutrophil receptors. GM-CSF signaling promotes a pro-inflammatory M1 macrophage phenotype and the production of a number of inflammatory cytokines and chemokines by monocyte-derived or tissue macrophages (black arrows). Macrophages themselves are direct targets of the SARS-CoV-2 via expression of the receptor for viral binding ACE2, as well as TMPRSS2 or a furin-like proprotein convertase. The effect of SARS-CoV-2 on macrophage phenotype is not defined, although inhibition of protective interferon signaling is reported. Lung macrophages also express the G protein-coupled alpha 7 nicotinic receptors (nAChRs α7) that signal through JAK-STAT3 and oppose inflammatory signaling by blocking the translocation of p65/p50 NF-κB into the nucleus upon IκBα (inhibitor of NF-κB) degradation. See text for additional details. Some of the content is adapted from Servier Medical Art (https://smart.servier.com/).