Degradation of IL-4Ralpha by Immunoproteasome: implication in airway type 2 inflammation and hyperresponsiveness.

Abstract

Introduction: Immunoproteasome (IP) is induced by pro-inflammatory stimuli such as interferon gamma to regulate inflammation and immunity. Asthma patients with airway type 2 high inflammation (e.g., IL-13) demonstrate more eosinophils and airway hyperresponsiveness (AHR) with less interferon gamma. The role of IP in regulating airway eosinophilic inflammation and AHR has not been investigated.

Methods: This study was aimed to determine how IP regulates type 2 inflammation and AHR using LMP7 (a subunit of IP) deficient mouse lungs, precision-cut lung slices (PCLS), and cultured human airway epithelial cells treated with IL-13 in the absence or presence of an IP inhibitor ONX-0914 or exogenous IP.

Results: LMP7 KO mouse lungs had significantly more IL-4Rα protein expression than the wildtype (WT) mice. Following IL-13 treatment in PCLS, LMP7 KO mice had significantly more airway contraction than WT mice, which was coupled with increased eotaxin-2 levels. IP inhibition by ONX-0914 in IL-13 treated human airway epithelial cells resulted in significantly more IL-4Rα protein expression and eotaxin-3 release. IP inhibition in human PCLS significantly increased AHR.

Conclusion: Collectively, these data demonstrated that IP promotes degradation of IL-4Rα, while inhibits type 2 inflammation and AHR. Enhancement of IP expression or activity may serve as an alternative approach to reduce the severity of type 2 inflammation and AHR.