Allergen-dependent solubilization of IL-13 receptor α2 reveals a novel mechanism to regulate allergy

Background: Allergic sensitization affects half of western populations and often precedes the development of allergic disorders including asthma. Despite the critical role of allergens in the pathogenesis of these disorders, little is known about how allergens modulate the immune response. IL-13 receptor alpha 2 (IL-13R alpha 2) is a decoy receptor for IL-13. Objective: Although the existence of soluble IL-13R alpha 2 has been documented, the mechanisms underlying its generation are unknown. Many allergens possess protease activity; we investigated whether IL-13R alpha 2 is solubilized in response to allergen treatment. Methods: We evaluated the ability of allergens to solubilize IL-13R alpha 2 in vitro and in vivo and examined the effect on IL-13 signaling and responses. Results: We determined that treatment of cells with house dust mite (HDM) allergen or purified Dermatophagoides pteronyssinus or Dermatophagoides farinae, but not other allergens, resulted in release of soluble IL-13R alpha 2 that was biologically active and inhibited IL-13 signaling. Prolonged exposure to HDM or treatment with mold allergens resulted in IL-13R alpha 2 degradation. This was associated with increased IL-13 signaling. A single treatment of HDM in vivo resulted in release of IL-13R alpha 2 into the bronchoalveolar lavage (BAL) fluid. BAL fluid from humans also contained IL-13R alpha 2; BAL fluid from individuals with asthma contained less IL-13R alpha 2 than that from controls. Conclusion: Allergen exposure can directly affect the level of soluble IL-13R alpha 2 in a way that affects IL-13 signaling and responses. Clinical implications: Soluble IL-13R alpha 2 may be an important biomarker of environmental allergen exposure and asthma.