PMC:7546716 / 47239-49652 JSONTXT

{"target":"https://pubannotation.org/docs/sourcedb/PMC/sourceid/7546716","sourcedb":"PMC","sourceid":"7546716","source_url":"https://www.ncbi.nlm.nih.gov/pmc/7546716","text":"Upon increasing release of alarmin IL-33 from injured respiratory cells, in the lack of interferon expression, and alongside efforts of the immune system to overcome inefficient natural killer cells, cytotoxic T lymphocytes, and Th1 antiviral responses, sequential compensatory secretion of IL-2 family cytokines (ie. IL-4, IL-9, IL-2, IL-7) from dysregulated GATA3+ Treg cells, differentiated ILC2, and overstimulated antigen-presenting cells might account for the early expansion of polyfunctional (CXCR3+)Vγ9Vδ2 T cells and the later expansion of (CCR2+CCR5+) GM-CSF-producing lymphocytes, both recruited to the lungs by specific chemoattractants. These cells amplify alveolar damage and establish autoinflammatory lung disease. At advanced stages of COVID-19, intense activation of the NLRP3 inflammasome and TLR2–MyD88–NF-κB mediated pathways most likely create a cytokine environment enriched in IL-1β, IL-23, IL-6, and TNF, which would further elicit Th17 differentiation and GM-CSF production by γδT17, Th17, and CD8 T cells (figure 1). Ultimately, the resulting cytokine and chemokine milieu could account for the hyperinflammatory state of tissues and vessels mediated by dysfunctional endothelial cells, mast cells, monocyte-derived macrophages, and extracellular trap-producing neutrophils. Endothelial release of tissue factor induced by IL-33, activated γδT cells, and neutrophil extracellular traps might act to promote thrombotic manifestations. In patients who survive acute COVID-19, IL-33 might finally drive pulmonary fibrosis by activating M2 macrophages, ILC2, and mast cells to release TGFβ and IL-13, which act in turn on fibroblasts and type 2 pneumocytes to elicit an epithelial-to-mesenchymal transition (figure 2). As a result, different stages of COVID-19 disease can be distinguished (ie, mild-to-moderate, severe-to-critical, chronic-to-fibrotic), and we suggest that IL-33 plays a central role in all of these pathogenic phases (figure 3). A preprint101 that recently appeared online supports our model, revealing that SARS-CoV-2 peptide exposure elicits IL-33 expression from patients who are virus seropositive, and IL-33 production is correlated with T-cell activation and lung disease severity. Targeting the IL-33–ST2 axis using monoclonal antibodies (or, alternatively, small-molecule inhibitors) could prove to be an effective strategy for controlling the COVID-19 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