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.