Pathological inflammation in patients with COVID-19: a key role for monocytes and macrophages

Abstract

The COVID-19 pandemic caused by infection with SARS-CoV-2 has led to more than 200,000 deaths worldwide. Several studies have now established that the hyperinflammatory response induced by SARS-CoV-2 is a major cause of disease severity and death in infected patients. Macrophages are a population of innate immune cells that sense and respond to microbial threats by producing inflammatory molecules that eliminate pathogens and promote tissue repair. However, a dysregulated macrophage response can be damaging to the host, as is seen in the macrophage activation syndrome induced by severe infections, including in infections with the related virus SARS-CoV. Here we describe the potentially pathological roles of macrophages during SARS-CoV-2 infection and discuss ongoing and prospective therapeutic strategies to modulate macrophage activation in patients with COVID-19.

Conflict of interest statement

The authors declare no competing interests.

Figures

Fig. 1. Possible pathways contributing to hyperactivation of monocyte-derived macrophages and hyperinflammation in COVID-19.

Several mechanisms likely contribute to the hyperactivation of monocyte-derived macrophages that is seen in patients with COVID-19. Delayed production of type I interferon leading to enhanced cytopathic effects and increased sensing of microbial threats promotes the enhanced release of monocyte chemoattractants by alveolar epithelial cells (and likely also by macrophages and stromal cells), leading to sustained recruitment of blood monocytes into the lungs. Monocytes differentiate into pro-inflammatory macrophages though activation of Janus kinase (JAK)–signal transducer and activator of transcription (STAT) pathways. Activated natural killer (NK) cells and T cells further promote the recruitment and activation of monocyte-derived macrophages through the production of granulocyte–macrophage colony-stimulating factor (GM-CSF), tumour necrosis factor (TNF) and interferon-γ (IFNγ). Oxidized phospholipids (OxPLs) accumulate in infected lungs and activate monocyte-derived macrophages through the Toll-like receptor 4 (TLR4)–TRAF6–NF-κB pathway. Virus sensing can trigger TLR7 activation through viral single-stranded RNA recognition. It is possible that type I interferons induce the expression of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) entry receptors, enabling the virus to gain access to the cytoplasm of macrophages and to activate the NLRP3 inflammasome, leading to the secretion of mature IL-1β and/or IL-18. IL-1β can amplify activation of monocyte-derived macrophages in an autocrine or paracrine way, but it can also reduce type I interferon production in infected lungs. The engagement of Fcγ receptors (FcγRs) by anti-spike protein IgG immune complexes can contribute to increased inflammatory activation of monocyte-derived macrophages. Activated monocyte-derived macrophages contribute to the COVID-19 cytokine storm by releasing massive amounts of pro-inflammatory cytokines. CCL, CC-chemokine ligand; CXCL10, CXC-chemokine ligand 10; ISG, interferon-stimulated gene; ITAM, immunoreceptor tyrosine-based activation motif; TRAM, TRIF-related adaptor molecule.

Fig. 2. Possible contribution of hyperactivated monocytes to coagulation in COVID-19.

Circulating pro-inflammatory stimuli, such as viral pathogen-associated molecular patterns (PAMPs), damage-associated molecular patterns (DAMPs) and cytokines trigger activation of blood monocytes, which respond by inducing tissue factor membrane expression. Endothelial cells are activated by cytokines and viral particles and produce monocyte chemoattractants and adhesion molecules. Endothelial damage induced by the virus can also expose tissue factor on endothelial cells. Activated monocytes are recruited to endothelial cells. Tissue factor expressed by activated monocytes, monocyte-derived microvesicles and endothelial cells activates the extrinsic coagulation pathway, leading to fibrin deposition and blood clotting. Neutrophils are recruited by activated endothelial cells and release neutrophil extracellular traps (NETs), which activate the coagulation contact pathway and bind and activate platelets to amplify blood clotting. Major endogenous anticoagulant pathways, which include tissue factor pathway inhibitor (TFPI), antithrombin and protein C, are reduced further, supporting coagulation activation. CCL2, CC-chemokine ligand 2; SARS-CoV-2, severe acute respiratory syndrome coronavirus 2; TLR, Toll-like receptor; TNF, tumour necrosis factor; vWF, von Willebrand factor.