IL-33 has also been shown to stimulate expression of IL-1β, IL-6, CCL2, CXCL2, and G-CSF by adipocytes.57 Elevated circulating concentrations of soluble ST2 (measured more often than IL-33 because of its higher concentration and stability) are associated with obesity, diabetes, hypertension, and acute cardiovascular diseases. High soluble ST2 concentrations also predict worse outcomes and are associated with extension of heart damage, heart failure, increased cardiovascular death, and all-cause mortality.54 Notably, diabetes, hypertension, and cardiovascular diseases are common comorbidities in patients with COVID-19, and obesity has been independently associated with increased severity and mortality among younger patients with COVID-19.66 Circulating concentrations of soluble ST2 correlate with the extent of tissue damage, and might represent an indicator in plasma of IL-33 release and bioactivity in tissues. Production of soluble ST2 might be reduced by anti-ST2 treatment, and such reduction would modulate T-cell polarisation by decreasing pathogenic Th1 and Th17 cells, and increasing IL-10-producing Treg cells.67 Future research should focus on whether soluble ST2 concentrations in plasma have prognostic value in patients with COVID-19 (figure 2 ).
Figure 2 IL-33 might orchestrate all pathogenic phases of COVID-19
IL-33 might induce numerous cytokines and chemokines as well as its own receptor, ST2, in various cell types. In asymptomatic or paucisymptomatic patients, IL-33 might expand anti-inflammatory Foxp3+ Treg cells or induce IL-4 production by GATA3+Foxp3+ Tregs and ILC2, thus stimulating mast cells, which might account for minor, allergy-like symptoms. In individuals with mild-to-moderate disease, IL-33 (along with TGFβ) might induce ILC2 to release large amounts of IL-9, driving local expansion of effector memory Vγ9Vδ2+ T cells in the lungs. In moderate–to-severe pneumonia, IL-33 combined with IL-2 and IL-7 from dendritic cells might further expand ILC2, γδT cells, and GM-CSF-producing T cells. In severe–critical COVID-19, IL-33, GM-CSF, and IL-1 might stimulate each other's release by acting on multiple cell types. IL-33 induction of cytokines, chemokines, adhesion molecules, tissue factor, and neutrophil extracellular traps might contribute to endothelialitis, thrombosis, and extrapulmonary involvement in patients with MAS-like disease. Neutrophil extracellular traps and mast cell degranulation could provoke protease-mediated cleavage of IL-33 into a 10–30 times more potent form, and IL-33-induced release of its soluble receptor ST2 might further polarise T cells and contribute to cardiovascular manifestations. In patients who survive, IL-33 might drive the post-acute fibrotic phase thorugh induction of IL-13 and TGFβ in M2-differentiated macrophages and ILC2, thereby stimulating myofibroblasts and eliciting the epithelial–to–mesenchymal transition of type 2 pneumocytes. Molecules inside brackets are part of self-amplifying proinflammatory loops fed by IL-33 and outside brackets indicate different factors possibly induced by IL-33. Question mark indicates the uncertainty of whether mast cells produce IL-33. bFGF=fibroblast growth factor. CCL=C-C motif chemokine ligand. CTGF=connective tissue growth factor. CXCL=C-X-C motif chemokine ligand. DIC=(systemic vascular thromboses mimicking) diffuse intravascular coagulation. EMT=epithelial-mesenchymal transition. Foxp=forkhead box protein. GATA=GATA-binding factor. G-CSF=granulocyte colony-stimulating factor. GM-CSF=granulocyte-macrophage colony-stimulating factor. ICU=intensive care unit. IFN=interferon. IL=interleukin. ILC2=type 2 innate lymphoid cell. MAS=macrophage activation syndrome. MOF=multiple organ failure. NET=neutrophil extracellular trap. PDGF=platelet-derived growth factor. P/F ratio=arterial oxygen partial pressure to fractional inspired oxygen ratio. sST2=soluble ST2. ST2=ST2 receptor. TGF=transforming growth factor. TF-1=tissue factor-1. TNF=tumour necrosis factor. TRAIL=TNF-related apoptosis-inducing ligand. Treg=regulatory T cell.