IL-33 induction of pulmonary fibrosis in chronic COVID-19
Lung alveolar inflammation in COVID-19 is accompanied by loose interstitial fibrosis and can result in widespread fibrotic changes.79 IL-33 could also be important at these later stages of the disease. In a bleomycin-induced pulmonary fibrosis mouse model, the IL-33–ST2 axis is required to induce alternatively activated M2 macrophages and ILC2 to release key profibrotic cytokines.80 IL-33-activated mast cells might also play a role in organ fibrosis.81 Most remarkably, IL-33 has been shown to induce epithelial-to-mesechymal transition of type 2 pneumocytes through TGFβ signalling.82
IL-33 concentrations are elevated in patients with systemic sclerosis and correlate with the severity of pulmonary fibrosis, and patients with idiopathic pulmonary fibrosis show increased serum concentrations of soluble ST2 when the disease is exacerbated.82 IL-33 can induce cytokines (eg, TGFβ, IL-13) and chemokines (eg, CCL2, CXCL6) involved in pulmonary fibrosis, which are also increased in patients infected with SARS-CoV-2,6, 9, 11, 15, 26 thus suggesting additional roles for IL-33 in driving the post-acute fibrotic phase of COVID-19. Growth factors such as vascular endothelial growth factor, platelet-derived growth factor, and fibroblast growth factor are all involved in fibrotic processes and are overexpressed in patients with COVID-19,9 and γδ T cells exposed to TGFβ might produce connective tissue growth factor (figure 2).83