Abstract Rationale COPD is a heterogeneous disease defined by persistent inflammation and airflow limitation. A significant subset of patients display elevated type 2 inflammation as characterized by increased eosinophils in blood or sputum and/or elevated fractional exhaled nitric oxide. The clinical efficacy of dupilumab in COPD highlights the role of IL-4Rα and its ligands, IL-4 and IL-13, in disease pathogenesis. However, the tissue-specific distribution of these cytokines and their cellular targets in COPD lungs remains poorly understood. In this study, we aim to systematically map the localization of IL-4, IL-13, IL-4Rα, as well as eosinophils within lung compartments and lung-draining lymph nodes of COPD patients across a spectrum of COPD severity. Methods Lung tissue was surgically obtained from 41 COPD patients (GOLD stages I-III, n = 17; GOLD stage IV, n = 24), and 36 healthy controls. Tissue eosinophils were identified using immunohistochemistry and fluorescence in situ hybridization was used to detect the presence of mRNA for IL-4, IL-13, and IL-4Rα. Results IL-4Rα is predominantly expressed by structural cells and immune cells, while its ligands, IL-4 and IL-13, are mainly produced by immune cells. In both controls and patients with COPD, our analyses revealed constitutive expression of IL-4Rα across multiple lung compartments, including the large and small airways, alveolar parenchyma, and lung-draining lymph nodes. Notably, the expression levels of IL-4Rα were significantly higher in patients with severe COPD (GOLD stage IV) compared to those with milder disease (GOLD stages I-III). Tissue samples from COPD patients are typically collected during periods of stable disease. Consistent with this, the expression of IL-4 and IL-13 in the airways and alveoli was generally low, although detectable above the negative probe background. In contrast, robust expression of IL-4, IL-13, and IL-4Rα was observed in lung lymphoid aggregates and draining lymph nodes across all GOLD stages, indicating these sites may serve as active arenas for type 2 inflammation in COPD. Furthermore, a subset of samples from severe GOLD stage IV patients displayed evidence of markedly heightened airway immune cell infiltration, suggesting recent exacerbation. In one such case involving active eosinophilic bronchitis, cells expressing both IL-4 and IL-13 were prominently detected in the airway epithelium and subepithelium. These dual-expressing cells could be found either adjacent to or separate from areas of dense eosinophilic infiltration. Conclusion The involvement of the IL-4/IL-13/IL-4Rα pathway across multiple lung compartments and extrapulmonary lymph nodes suggests broad potential mechanistic areas of interest for IL-4Rα-targeting biologics in COPD. This abstract is funded by: Regeneron Pharmaceuticals
Casey et al. (Fri,) studied this question.