View Abstract

A1305 - The Soluble IL-22 Decoy Receptor, IL-22Ra2, Promotes Allergic Airway Disease Pathogenesis
Author Block: M. L. Manni1, M. D. Pilarski1, D. B. Ukani1, S. N. Patel1, K. J. McHugh1, D. A. Pociask2, J. K. Kolls3, J. F. Alcorn1; 1Pediatrics, Children's Hospital of Pittsburgh of UPMC, Pittsburgh, PA, United States, 2Pulmonary Critical Care and Environmental Medicine, Tulane University School of Medicine, New Orleans, LA, United States, 3Center for Translational Research in Infection and Inflammation, Tulane University School of Medicine, New Orleans, LA, United States.
RATIONALE: Asthma is a complex heterogeneous disease affecting approximately 300 million people worldwide and there are no preventions or cures. As nearly 50% of asthmatics do not display canonical type 2 or eosinophilic-dominant inflammation, there is a need to investigate other subsets of disease. In severe refractory disease, allergen-specific, steroid-insensitive T helper (Th) 17 and/or Th2 cells are thought to critically orchestrate the hallmarks of asthma pathogenesis (pulmonary inflammation, mucus hypersecretion, and airway hyperresponsiveness (AHR)). Further, the Th17 immune cytokine interleukin (IL)-22 is known to play a vital role in maintaining epithelial integrity and promoting repair, especially in the lung. In OVA models of allergic airway disease, IL-22 is thought to play a dual role in disease pathogenesis, having both pro- and anti-inflammatory effects depending on disease stage. Interleukin-22 receptor alpha-2 (IL-22Ra2) is a soluble receptor for IL-22 that inhibits its activity, and thus may serve as a critical regulator for this cytokine in vivo. However, the significance of IL-22 and endogenous IL-22Ra2, as well as the pathways that regulate them in the lung, are unknown. This study seeks to elucidate the role of IL-22Ra2 in allergic airway disease.
METHODS: To investigate the involvement of IL-22 soluble decoy receptor in disease pathogenesis, wild-type and IL-22Ra2-/- mice were sensitization and challenged with house dust mite extract or adoptively transferred with ovalbumin-specific Th2 and Th17 to induce allergic airway disease. Allergic airway disease was then evaluated by assessing pulmonary inflammation, baseline lung function and AHR to methacholine challenge using flexiVent, and mucus production in the airways.
RESULTS: Mice lacking IL-22Ra2 had less airway inflammation and pulmonary expression of Th2- and Th17-related cytokines when compared to wild-type mice in both Th2/Th17- and HDM-induced allergic airway disease. Further, IL-22Ra2-/- mice had lower AHR than wild-type mice with allergic airway disease.
CONCLUSION: Overall, these studies revealed that IL-22Ra2-/- mice were protected from allergic airway disease when compared to wild-type mice, suggesting IL-22Ra2 may promote allergic airway disease pathogenesis. Further studies are warranted to develop a better understanding of IL-22Ra2 production and regulation in the lungs as well as its importance in IL-22 regulation.