Altered Site-Specific Expression Patterns of Interleukin-33 and Its Receptor ST2 in COPD Lungs

Background: Basic information is missing on the actual expression patterns of the alarmin IL33 and its receptor ST2 inside human normal and diseased lung tissues. Aims: To reveal the anatomical localization, cellular distribution, and dynamics of IL33 mRNA, IL33 protein, and soluble and membrane-bound ST2 across COPD severities. Methods: Surgical lung tissue was collected from 38 COPD patients and 18 controls. IL33 and ST2 expressing cell types were assessed in histological sections by single-combined in situ hybridization (ISH-IHC) and cutting-edge multiplex immunohistochemistry (mIHC). The expression dynamics of ST2 variants and IL33 was explored by spatially resolved single cell analysis. Results: Both IL33 mRNA and protein was confined to structural cells. Compared to controls, IL33 mRNA levels in COPD displayed a more robust increase than IL33 protein. Consequently, the IL-33 mRNA/protein ratio was significantly increased in multiple lung compartments. ST2 mRNA levels were also broadly upregulated in COPD lungs. Although membrane ST2 mRNA was detected in multiple leukocytes, mast cell was the by far dominating expressing cell type. Intriguingly, patchy consolidated lung regions in COPD displayed upregulated soluble ST2 in alveolar capillaries. Conclusions: The increased ratio IL33 mRNA / protein ratio provides further evidence that this pathway is activated in COPD. Our data also point out lung mast cells and alveolar capillaries as key regulators of IL-33-mediated immunity in COPD-affected lungs. Apart from exposing the structural basis for IL33-mediated inflammation in human lungs, our data have important bearings to treatments strategies targeting this pathway in lung diseases.