Lung IL-33 Levels Depleted in COVID-19

RATIONALE: Interleukin-33 (IL-33) is a danger signaling alarmin with an integral role in wound repair, fibrosis, and remodeling processes. IL-33 is increased in the serum and airways in patients with chronic obstructive pulmonary disease (COPD) and in lung tissues of patients with idiopathic pulmonary fibrosis (IPF). Recently, elevated serum IL-33 levels have been associated with poor outcomes with severe acute respiratory syndrome coronavirus (SARS-CoV)-2, although there have been no studies examining IL-33 expression from involved lung tissues. The objective of this study was to characterize IL-33 expression in lung tissues of patients with severe COVID-19, comparing tissue expression with that observed in other inflammatory lung diseases. METHODS: Post-mortem lung sections of de-identified patients with COVID-19 (N=8), COPD (N=6), IPF (N=4), and from normal subjects (N=7) deemed unsuitable for transplant were stained for IL-33 with prosurfactant protein C (proSP-C), a marker of type II alveolar epithelial cells (AT2), or with vimentin, a mesenchymal cell marker increased with fibrosis. With fluorescence microscopy, 10 photographs of each section/patient were taken. Images were quantitated by measuring integrated densities (the product of area and mean gray value) of each protein with Image J. Averaged integrated densities of each patient were plotted for statistical analysis with Prism 9 using Mann-Whitney test versus control group with p<0.05 accepted as statistically significant. RESULTS: Tissue IL-33 expression was increased in IPF (6.57-fold, p=0.0012) and COPD (3.91-fold, p=0.0012) compared to control lungs, whereas COVID-19 patients had low to negligible lung IL-33 expression that was markedly reduced as compared to controls (0.03-fold;p=0.0003). Vimentin staining was increased in COVID-19 (2.15- fold, p=0.0093) and IPF (1.74-fold, p=0.0424) lungs as compared to controls with no difference between COPD and controls. AT2 was decreased in COVID-19 (0.01-fold, p=0.0003) and COPD (0.43-fold, p=0.0047) lungs marked by decrease in proSP-C staining with no difference between IPF and controls. CONCLUSIONS: These studies confirm an increase in expression of IL-33 in chronic lung diseases yet demonstrate a striking depletion of lung tissue IL-33 in severe COVID-19 coupled with increased vimentin staining and decreased AT2 cells. Because recent studies have demonstrated that serum IL-33 levels are increased at the time of hospital admission with COVID-19, longitudinal studies of convalescent patients would provide insight into how IL-33 might mediate SARS-CoV-2-induced adverse lung pathophysiology and/or recovery. Understanding the mechanisms and timing of IL-33 expression in biological compartments and regulation for promoting damage or driving wound repair processes could inform potential interventional strategies.