Reciprocal regulation of lung resident alveolar macrophage function and repopulation by β-catenin and PPAR-γ dictates host morbidity and tissue recovery from respiratory viral infection

Abstract

Abstract Acute respiratory viral infections, such as influenza and respiratory syncytial virus infections, cause severe morbidity and mortality in children and the elderly worldwide. Lung resident alveolar macrophages (AM), residing in the alveolar space, have been recently shown as a critical regulator of host antiviral defense and the maintenance of normal lung function during acute respiratory viral infection. However, relatively less is known about the molecular regulation of AM function and repopulation in situ, and the roles of AM in the restoration of lung homeostasis at the recovery stage following pathogen clearance. Here we show that two reciprocally regulated transcription factors in AM, β-catenin and PPAR-γ, oppositely modulate host diseases and recovery following respiratory viral infection. AM β-catenin ablation results in reduced morbidity, accelerated inflammation resolution and recovery; while AM PPAR-γ deletion or constitutive β-catenin activation leads to enhanced diseases and impaired recovery following influenza and respiratory syncytial virus (RSV) infection. Mechanistically, β-catenin and PPAR-γ oppositely regulate AM antiviral, inflammatory, reparative, and immunological gene programs. Further, β-catenin and PPAR-γ distinctly modulate AM proliferation and repopulation, thereby regulating tissue recovery following infection. Strikingly, combined deficiency reveals that the main functions of β-catenin and PPAR-γ are based on mutual antagonism. Our data have revealed the critical roles of a transcriptional circuit in balancing rMΦ function and regeneration for the proper restoration of normal tissue homeostasis following infection.