Unveiling the Roles of Mast Cells and Endothelial Cells in IL-33/ST2 Pathway Dysregulation in COPD Lungs

Highlight

• Increased IL-33 expression and altered IL-33 turnover identified in distal lung regions of COPD patients compared to controls.
• Mast cells are the primary immune cells expressing the IL-33 receptor ST2 and show microenvironment-specific upregulation of both membrane-bound (ST2L) and soluble (sST2) variants in COPD lungs.
• Endothelial cell subsets, including general capillary (gCap) and aerocyte endothelia, also participate in IL-33/ST2 signaling, exhibiting distinct expression patterns influenced by COPD pathology.
• Spatially resolved single-cell analyses reveal patchy alveolar regions with elevated capillary sST2 and increased ST2L+ and IL-33+ gCaps in COPD, suggesting localized immune responses.

Study Background and Disease Burden

Chronic obstructive pulmonary disease (COPD) is a prevalent and progressive respiratory condition characterized by airflow limitation and chronic inflammation affecting small airways and lung parenchyma. Despite advances in understanding COPD pathobiology, the intricate cellular and molecular mechanisms driving persistent inflammation and tissue remodeling remain incompletely defined. IL-33, a member of the interleukin-1 cytokine family, has emerged as a crucial alarmin released upon cellular stress or damage, with pivotal roles in promoting type 2 immune responses and modulating airway inflammation. The IL-33 receptor, ST2, exists as two splice variants: the membrane-bound receptor ST2L, which mediates IL-33 signaling, and the soluble decoy receptor sST2, which neutralizes IL-33 activity. Dysregulation of the IL-33/ST2 axis has been implicated in asthma and other lung diseases, but its precise involvement in COPD, especially within anatomically critical small airways and distal lung compartments, is poorly understood. Clarifying which tissue cells express IL-33 and ST2 variants in COPD lungs is essential to elucidate disease mechanisms and identify potential therapeutic targets.

Study Design

This investigative study examined surgically excised lung tissues from 38 patients diagnosed with COPD and 21 non-COPD control subjects. The focus was placed on the distal lung compartments, which include poorly studied small airways and alveolar regions critical in COPD pathogenesis. The research utilized combined in situ hybridization and multiplex immunohistochemistry to detect and localize IL-33, ST2L, and sST2 mRNA and protein expression at the cellular level. Additionally, spatially resolved single-cell analyses were employed to detail the expression dynamics across lung cell populations, providing high-resolution insight into cellular heterogeneity and microenvironment-specific responses.

Key Findings

The study revealed several novel and clinically relevant insights into the IL-33/ST2 pathway within COPD lungs:

• Upregulation of IL-33 and ST2: COPD lungs exhibited increased IL-33 mRNA expression alongside elevated IL-33 mRNA to protein ratios, indicative of enhanced IL-33 turnover or processing activity. Total mRNA levels of ST2 (IL1RL1) were also significantly higher in COPD lungs compared to controls, suggesting an active regulatory axis in diseased tissue.
• Mast cells as central ST2-expressing immune effectors: Mast cells emerged as the predominant ST2-expressing immune cells in the lung tissue of both COPD patients and controls. Notably, in COPD lungs, mast cells showed microenvironmental-specific upregulation of both ST2L and sST2 variants, implying an adaptive or pathological modulation of IL-33 signaling capacity within the inflammatory niche.
• Endothelial cell subsets compartmentalize IL-33 and ST2 expression: In alveolar regions of control lungs, ST2L(high) and sST2(high) mast cells coexisted with IL-33-expressing general capillary endothelial cells (gCaps) and aerocyte endothelial cells characterized by moderate sST2 and low ST2L expression. COPD lungs demonstrated patchy alveolar regions with markedly elevated sST2 in capillaries and increased numbers of ST2L-positive and IL-33-positive gCap endothelial cells, revealing a disturbed balance and spatial heterogeneity in endothelial immune regulation.
• Spatial and cellular heterogeneity in distal lung IL-33/ST2 axis: Single-cell spatial analyses confirmed distinctive cellular expression patterns and localized regions with prominent alterations in IL-33 and its receptor variants, emphasizing the complexity of lung immune microenvironments contributing to COPD pathogenesis.

Expert Commentary

These findings significantly advance our understanding of COPD immunopathology by pinpointing the cellular sources and targets of IL-33 signaling within the distal lung. Mast cells’ upregulation of ST2 splice variants suggests their dual role as both responders to and modulators of IL-33-driven inflammation, potentially influencing airway remodeling and exacerbations. Endothelial cells, often underestimated in immune regulation, are shown here as active participants that may regulate local inflammatory dynamics via IL-33/ST2 interactions. Given the therapeutic interest in targeting the IL-33/ST2 axis in allergic and inflammatory airway diseases, these nuanced insights into cellular expression patterns provide a valuable framework for developing treatments tailored to COPD’s distal lung pathology.

However, it should be noted that the study’s cross-sectional design using surgical samples limits conclusions about temporal dynamics and causality. Further longitudinal studies and functional assays are warranted to link these expression patterns to clinical outcomes, exacerbation frequency, and response to IL-33-targeted therapies that are currently emerging in clinical trials.

Conclusion

This comprehensive investigation delineates the complex interplay of IL-33 and its receptor splice variants ST2L and sST2 in COPD lungs, with mast cells and endothelial cells as key mediators in distal lung compartments. The altered expression and spatial heterogeneity of these immunomodulatory molecules underscore their importance in COPD pathogenesis and highlight new avenues for targeted therapeutic strategies aimed at modulating IL-33/ST2 signaling. These insights broaden our molecular understanding of COPD and may contribute to improved precision medicine interventions in chronic airway diseases.

Funding and ClinicalTrials.gov

The study was supported by institutional grants and collaborations as detailed in the original publication by Andersson et al. (2026). No specific clinical trial registration number was indicated for this tissue-based exploratory research.

References

• Andersson CK, Siddhuraj P, Jönsson J, et al. Mast cells and endothelial cells mediate interleukin-33 and ST2 responses in distal chronic obstructive pulmonary disease lungs. Am J Respir Crit Care Med. 2026 Jul 1;212(7):1495-1509. doi:10.1164/rccm.202601-0034OC. PMID: 42085217.
• Prefontaine D, Lajoie-Kadoch S, Foley S, et al. Increased IL-33 expression by epithelial cells in bronchial asthma. J Allergy Clin Immunol. 2009 May;123(5):1171-3. doi:10.1016/j.jaci.2009.01.052.
• Kotla S, Yang L, Choi JH, et al. Endothelial cell regulation of immune responses. Curr Opin Immunol. 2021 Aug;69:100-109. doi:10.1016/j.coi.2021.02.001.