Fig. 2

Suggested pattern for cell interactions in COVID-19, leading to pulmonary edema. In ECs, ACE2, CD147, NRP1, TLRs, L-SIGN, TMPRSS2, and sialic acid receptors may mediate SARS-CoV-2 penetration. PAF is released by a variety of cell types. ECs express PAFR. PAF/PAFR complex in ECs induces the production of cytokines such as CXCL1, TNF-α, IFN-γ, and IL-6. ECs may have TNFRs that cause surface expression of ICAM-1, E-selectin, and VCAM-1. In adherens junctions, important cytosolic partner(s) for VE-cadherin are α- and β-catenin and for nectins is afadin. TNF inhibits the expression of VE-cadherin, blocks its contact with β-catenin, affects actin cytoskeleton remodeling, and activates the NF-κB pathway, resulting in elevated expression of inflammatory genes. Some tight-junction-associated proteins include occludin, claudins, jAMs, ZO1, ZO2, ZO3, and PALS1 (A). SARS-CoV-2 E protein interacts with PALS. TNF disrupts claudin-5. TNF-α destroys JAM-A, claudin-4, and claudin-5. EC death occurs by apoptosis and/or necrosis. In the extrinsic pathway, TRAILR and Fas stimulation cause caspase-8 activation. Caspase-8 stimulates the caspase cascade that ultimately leads to apoptosis. FasL is released by neutrophils and lymphocytes. NK cells and cytotoxic T cells secrete perforin and granzymes that, through direct exposure to target cells, secrete perforin and granzymes, resulting in induction of apoptosis and/or necrosis. The molecular mechanism of necrosis is not clear, though it probably occurs via the release of lysosomal enzymes and generation of ROS, and in necrosis significant ATP depletion is seen. Fas and TNF stimulate both apoptosis and necrosis. ECs release t-PA, mediating the conversion of plasminogen to plasmin, and MMPs, lysing ECM. t-PA enhances neutrophil degranulation and MMP-9 secretion. Cell infiltration is facilitated by MMPs that result in leukopenia. Infected cells secrete numerous cytokines and DAMPs. DAMPs induce NETosis. NETs include DNA, histones, and enzymes such as serine protease. They are a scaffold for platelets, red blood cells (RBCs), and plasma proteins. Histones can activate pro-FSAP. FSAP, a serine protease, is a mediator of plasminogen-to-plasmin conversion. NETs activate FXII to convert prothrombin to thrombin. Thrombin converts fibrinogen to fibrin. Fibrin contributes to blood clot formation. Thrombin, NET serine proteases, and histones activate platelets. vWF is secreted by ECs and enhances platelet adhesion and aggregation. Basophils are secreted by IL-4, IL-6, and IL-13 production. They affect mature human B cells. IL-4 is correlated with the concentration of IgG antibodies, but IL-6 is inversely associated with them. Eosinophils produce NO and EETs to limit viral replication. NO inhibits platelet activation. On the other hand, EETs and MBP mediate platelet activation. Activated eosinophils secrete IL-2, IL-8, IL-12, and INF λ. EDN induces the TLR2–MyD88 signal pathway in DCs, resulting in IL-12, IL-27, and IL-18 secretion that increases NK cell activity and induces secretion of IFN-γ. IFN-γ is also secreted by NK cells. DCs also produces IL-6, significantly. ECP and EDN activate apoptotic pathways. ECP also stimulates necrosis process. In addition, increased levels of MBP and ECP stimulate the degranulation of perivascular MCs. MCs release IL-6, IL-1β, and TNF. NK cell activity can decrease by IL-6 and IL-1β. ROS can also be an inhibitor for NK cells. Eosinophils produce ROS. NK cells activate apoptosis and necrosis by secretion of FasL, TRAIL, perforin, and granzymes. B-cell and T-cell interactions lead to plasma cell generation (colonal expansion, antibody secretion) and production of either proinflammatory cytokines such as IL-12, IL-6 and IL-15 or anti-inflammatory cytokines such as IL-10, IL-35, and TGF-β by B cells. IL-12 and IL-6 provide positive feedback in B- and T-cell interactions. IL-15 enhances CD8⁺ T-cell activity. GM-CSF are produced by macrophages, B cells, T cells, NK cells, and ECs. GM-CSF stimulate the differentiation of monocytes. M1 produce proinflammatory cytokine such as IL-1β, IL-6, TNF-α, and IL-12 and INFs. M2 releases types I and III collagen, MMPs, and anti-inflammatory cytokines such as IL-10 or TGF-β. M2 can be transited into fibroblasts by TGF-β mediation, leading to pulmonary fibrosis. M1 stimulates Th cells. IFN-γ, TNF-β, and IL-2 are secreted by Th cells that activate macrophages. M1 activates NK cells by IL-1β, IFN-β, and IL-15. Alveolar macrophages release IL-1, IL-6, TNFs, and IL-8. Type 2 pneumocytes also play a major role in the formation of cytokine storms. Destruction of the air–blood barrier leads to infiltration of cells associated with alveolar epithelial cells secreting many cytokines, such as IL-1B, IL-2, IL-6, IL-7, IL-8, IL-10, IL-17, TNF, etc., out of control, resulting in further and further injury. Finally, lung edema and pulmonary failure occurs (B). COVID-19, coronavirus disease 2019; ACE2, angiotensin-converting enzyme 2; ECs, endothelial cells; CD147, cluster of differentiation 147; TLRs, Toll-like receptors; NRP1, neuropilin-1; L-SIGN, homolog dendritic cell-specific intercellular adhesion molecule-3-grabbing non-integrin related; serine 2; TMPRSS2, transmembrane protease, SARS-CoV-2, severe acute respiratory syndrome coronavirus 2; PAFR, platelet-activating factor receptor; PAF, platelet-activating factor; TNF, tumor necrosis factor; IL, interleukin; IFN, interferon; TNFRs, tumor necrosis factor receptor; ICAM-1, intercellular adhesion molecule-1; VCAM-1, vascular cell adhesion molecule-1; VE-cadherin, vascular endothelial cadherin; ZO, zonula occludens; JAMs, junctional adhesion molecules; E protein, envelope protein; PALS1, protein associated with LIN7 1, MAGUK family member; TRAIL, TNF-related apoptosis-inducing ligand; t-PA, tissue plasminogen activator; NK cells, natural killer cells; NF-κB, nuclear factor kappa-light-chain-enhancer of activated B cells; MMPs, matrix metalloproteinases; ECM, extracellular matrix; FSAP, factor VII activating protease; DAMPs, damage-associated molecular pattern; NETs, neutrophil extracellular traps; NO, nitric oxide; vWF, von Willebrand factor; EETs, eosinophil extracellular traps; EDN, eosinophil-derived neurotoxin; MBP, major basic protein; MyD88, myeloid differentiation factor 88; ECP, eosinophil cationic protein; DCs, dendritic cells; MCs, mast cells; GM-CSF, granulocyte–macrophage colony-stimulating factor; TGF-β, transforming growth factor beta; M1, type 1 macrophages; M2, type 2 macrophages; Th cells, T-helper cells