Imperfect storm: is interleukin-33 the Achilles heel of COVID-19?

Abstract

The unique cytokine signature of COVID-19 might provide clues to disease mechanisms and possible future therapies. Here, we propose a pathogenic model in which the alarmin cytokine, interleukin (IL)-33, is a key player in driving all stages of COVID-19 disease (ie, asymptomatic, mild-moderate, severe-critical, and chronic-fibrotic). In susceptible individuals, IL-33 release by damaged lower respiratory cells might induce dysregulated GATA-binding factor 3-expressing regulatory T cells, thereby breaking immune tolerance and eliciting severe acute respiratory syndrome coronavirus 2-induced autoinflammatory lung disease. Such disease might be initially sustained by IL-33-differentiated type-2 innate lymphoid cells and locally expanded γδ T cells. In severe COVID-19 cases, the IL-33-ST2 axis might act to expand the number of pathogenic granulocyte-macrophage colony-stimulating factor-expressing T cells, dampen antiviral interferon responses, elicit hyperinflammation, and favour thromboses. In patients who survive severe COVID-19, IL-33 might drive pulmonary fibrosis by inducing myofibroblasts and epithelial-mesenchymal transition. We discuss the therapeutic implications of these hypothetical pathways, including use of therapies that target IL-33 (eg, anti-ST2), T helper 17-like γδ T cells, immune cell homing, and cytokine balance.

Figure 1

T-cell polarisation in COVID-19 IL-33 released from virus-damaged cells might induce dysregulated GATA3⁺Foxp3⁺ Tregs and promote IL-2 production by dendritic cells, resulting in further expansion of Tregs. IL-33 might also elicit differentiation of ILC2, with TGFβ enhancing ST2 expression on these cells and facilitating production of IL-9. IL-9 in turn stimulates expansion of effector memory Vγ9Vδ2⁺ T cells with mixed Th1 and Th17 profiles that express CXCR3 and are recruited to the lungs by CXCL9 and CXCL10. IL-9 possibly induces its own transcription factor PU.1 and thus act in an autocrine and paracrine manner (along with TGFβ) to drive proliferation and survival of ILC2 and γδ T cells. Additional positive loops might be fed by IFNγ, which triggers production of CXCL9 and CXCL10 by macrophages. In severe forms of COVID-19, IL-33, along with IL-2 and IL-7 released by dendritic cells, might further stimulate T-cell expansion through STAT5 and induce production of large amounts of GM-CSF by γδ and T helper cells. At advanced stages of disease, aberrant activation of the MyD88-related NF-κB pathway and activation of the NLRP3 inflammasome might induce virus-exposed cells and infiltrating monocytes–macrophages to overproduce IL-1β, IL-23, and IL-6. IL-1β, IL-23, IL-6, and IL-7 act on STAT3 and RORC, thus promoting differentiation of CCR2⁺ T cells that are recruited to the lungs by CCL2 and CCL8 into γδT17 and Th17 cells producing IL-17 and GM-CSF. In turn, GM-CSF might further recruit and activate proinflammatory monocytes–macrophages. CCR=C-C motif chemokine receptor. CCL=C-C motif chemokine ligand. CXCL=C-X-C motif chemokine ligand. CXCR=C-X-C chemokine receptor. Foxp=forkhead box protein. GATA=GATA-binding factor. GM-CSF=granulocyte-macrophage colony-stimulating factor. IL=interleukin. ILC2=type 2 innate lymphoid cell. MyD88=myeloid differentiation primary response protein. NF-κB=nuclear factor-kappa B. NLRP=NACHT, LRR, and PYD domains-containing protein. PU.1=transcription factor PU.1. RORC=nuclear receptor ROR-gamma. ST2=ST2 receptor. STAT=signal transducer and transcription activator. TGF=transforming growth factor. Th=T-helper. TLR=toll-like receptors. Treg=regulatory T cell.

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.

Figure 3

Inflammatory patterns in COVID-19 at various disease stages Cytokine interplay between IL-33, GM-CSF, IL-1α, and IL-1β, and key cytokines, chemokines, and receptors, the composition of lung inflammatory infiltrates, cell phenotypes involved, and possible therapeutic options according to different stages of disease. CCR=C-C motif chemokine receptor. CCL=C-C motif chemokine ligand. CXCL=C-X-C motif chemokine. CXCR=C-X-C motif chemokine receptor. FABP=fatty acid-binding protein. FCN=ficolin. FGF=fibroblast growth factors. GATA=GATA-binding factor. GM-CSF=granulocyte-macrophage colony-stimulating factor. i=inhibitor. IFN=interferon. IL=interleukin. ILC2=type 2 innate lymphoid cell. JAK=Janus kinase. NLRP=NACHT, LRR, and PYD domains-containing protein. PDGF=platelet-derived growth factor. PDGF-Ri=platelet-derived growth factor receptor inhibitor. rIL=recombinant interleukin. SPP=secreted phosphoprotein. sST2= soluble ST2. ST2=ST2 receptor. TGF=transforming growth factor. Th=T-helper. TLR=toll-like receptor. Treg=regulatory T cell. VEGF=vascular endothelial growth factor.