Prostaglandin I2 signaling restrains Treg ST2 expression by repressing β-catenin in allergic airway inflammation

Abstract

Background: T regulatory cells (Treg) dampen immune activation. Treg downregulate the type 2 response to innocuous environmental antigens that produce allergic airway inflammation; however, ST2+ Treg promote allergic airway inflammation. We reported that prostaglandin I₂ (PGI₂), which signals through the G protein coupled receptor IP, promoted Treg function in an ovalbumin-based model of allergic airway inflammation and suggested a role for PGI₂ signaling through the IP receptor augmenting β-catenin activity in Treg.

Objective: Herein, we sought to define the mechanisms responsible for PGI₂'s promotion of Treg function in the context of an environmental allergen.

Methods: Treg specific IP-deficient mice, Treg fate-tracking IP deficient mice and Treg specific IP and β-catenin-deficient mice were exposed to an alternaria alternata (Alt) extract sensitization and challenge model. Bronchoalveolar lavage fluid was evaluated for cell number, cell differential and cytokines by ELISA. Lungs were evaluated by flow cytometry and histopathology.

Results: Utilizing Treg-specific IP-deficient mice, we found that loss of PGI₂ signaling impaired Treg suppressive function in response to Alt; specifically, we found enhanced type 2 cytokine production, eosinophil infiltration, vascular remodeling, and numbers of ST2+ Treg compared to controls. We found that dual IP and β-catenin deficiency in Treg prevented the enhanced type 2 response and the further increase in ST2+ Treg via prevention of an increase in GATA3 expression in response to Alt.

Conclusions: Together, these data further support the importance of PGI₂ signaling within Treg to their support functionality and demonstrate that PGI₂ prevents Treg dysfunction through downregulation of β-catenin.

Keywords: Prostaglandin I(2); ST2; Treg; alternaria alternata; inflammation; β-Catenin.