The Role of RUBCN in Exacerbating Allergic Airway Inflammation

Abstract Allergic airway inflammation (typified by atopic asthma) is a classic example of type 2 immunity, which can be triggered by non-microbial environmental stimuli, such as allergens. Importantly, type 2 immunity engages the entire affected tissue and can involve the activity of not only immune cells, like Th2 cells and eosinophils, but also non-hematopoietic cells, like epithelial cells. Often, type 2 immunity exists in competition with type 1 immunity, classically defined as the activity of phagocytic cells, such as classically activated “M1” macrophages, and IFNg-producing adaptive immune cells, like CD8+ T cells and Th1 cells. Our past studies have demonstrated that deficiency in LC3-associated phagocytosis (LAP), a non-canonical form of autophagy requiring Rubcn, results in increased type 1 inflammation across a variety of stimuli, suggesting that LAP represents an important mechanism to regulate the inflammatory response. How Rubcn deficiency affects the onset and severity of type 2 immunity, such as allergic airway inflammation, remains unknown. Here, we demonstrate that, in response to house dust extract (HDE)/OVA exposure, lungs from Rubcn−/− mice contain increased levels of Th1 and Tr17 cells (potent regulatory CD4+ T cells that co-express FOXP3 and RORg), decreased Th2 cells, and decreased neutrophils, resulting in overall protection from allergic airway pathology. Rubcn-deficiency was required in non-hematopoietic cells, presumably airway epithelial cells, to exert this protective effect. As approximately 50% of asthmatics suffer from corticosteroid-resistant, neutrophil-mediated inflammation, inhibition of RUBCN could represent a novel therapy for steroid-resistant asthmatics.