IL-33 and pathway synergisms in critical systemic COVID-19
In addition to NLRP3 stimulation and IL-1 release,47 substantial amounts of viroporins in patients with life-threatening COVID-19 might also account for extensive injury of alveolar epithelial cells and overproduction of IL-33.51 IL-33, IL-1α, and GM-CSF also stimulate each other's release by alveolar type 2 pneumocytes.52, 53 Accordingly, diffuse alveolar damage with alveolar denudation and reactive type 2 pneumocyte hyperplasia are histological hallmarks of COVID-19 with acute respiratory distress syndrome.4
Feedforward loops might also engage mast cells, macrophages, endothelial cells, T cells, and neutrophils.40, 54 Although whether mast cells and macrophages produce IL-33 is still up for debate,51 it is well established that mast cells, infiltrating neutrophils, and cytotoxic T lymphocytes secrete serine proteases (eg, tryptase, cathepsin G, elastase, granzymes) that cleave IL-33 released from damaged epithelial and endothelial barriers into a mature form of IL-33 that is 10–30 times more active.51 IL-33 amplifies lung inflammation by inducing various proinflammatory cytokines (eg, GM-CSF, IL-1β, IL-6, TNF, granulocyte colony-stimulating factor [G-CSF]), chemokines (eg, CXCL1, CXCL2, CXCL6, CXCL8, CCL2, CCL20), and adhesion molecules (eg, E-selectin, ICAM1, VCAM1) in several target cells.32, 54, 55, 56, 57 Conversely, by inhibiting type 1 interferons and IL-12p35, IL-33 might contribute to impaired antiviral cytotoxic responses.58 In models of MAS-like disease, IL-33 is a crucial contributor to the weight loss and hyperferritinaemia related to systemic hyperinflammation, and to the expansion of GM-CSF-producing CD8+ T cells, upregulation of IL-1β and IL-6, and tissue neutrophilia.32 These features are the same as key characteristics seen in patients with critical COVID-19.5, 15, 26
IL-33 has also been implicated in the formation of neutrophil extracellular traps during virus-induced asthma exacerbation.58 Similarly, neutrophil priming with GM-CSF might promote the production of neutrophil extracellular traps.59 By releasing neutrophil elastase and other proteinases, neutrophil extracellular traps could in turn cleave and further activate IL-33. These pathways might be relevant in patients with critical COVID-19, since neutrophilia and the neutrophil-to-lymphocyte ratio are associated with poor prognosis, and high concentrations of neutrophil extracellular traps have been detected in patients with COVID-19 admitted to hospital and receiving mechanical ventilation.60
Neutrophil extracellular traps might propagate inflammation and microvascular thrombosis in patients with COVID-19 and severe acute respiratory distress syndrome.60 Along with IL-33, IL-1, TNF, and other cytokines, neutrophil extracellular traps might increase endothelial permeability and induce a procoagulant phenotype in endothelial tissues by inducing expression of tissue factor,61, 62, 63 thus representing a possible link between hyperinflammation and hypercoagulability that could account for D-dimer elevation, pulmonary thrombosis, and microvascular manifestations affecting the heart, kidneys, and small bowel seen in patients with critical COVID-19.64, 65 Endothelialitis and endothelial dysfunction would also account for predominant exudative-phase diffuse alveolar damage characterised by hyaline membranes and fibrin deposits typically observed in patients with COVID-19 and severe acute respiratory distress syndrome.4
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.