COVID-19 Cytokine Storm Pathway
Activated monocyte-derived macrophages (MDM) 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. 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), tumor necrosis factor (TNF) and interferon-γ (IFNγ). Oxidized phospholipids (OxPLs) accumulate in infected lungs and activate MDMs through the Toll- like receptor 4 (TLR4)–TRAF6–NF-κB pathway. Virus sensing can trigger TLR7 activation through viral single-stranded RNA recognition. Type-I INF might induce the expression of Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2) entry receptors (ACE2, CD147), enabling the virus to access the macrophage cytoplasm and activate the NLRP3 inflammasome, leading to the secretion of IL-1β and/or IL-18. The engagement of Fcγ receptors (FcγRs) by anti-spike protein IgG immune complexes can contribute to increased inflammatory activation of MDMs.