Allergen-induced trained immunity in alveolar macrophages predisposes to long-lasting airway hypersensitivity

Allergic asthma is characterized by airway hypersensitivity to various allergens and chronic airway inflammation. The mechanisms underlying such a prolonged and broad-responsive airway hypersensitivity remain not fully understood. In this study, we systematically investigated the role of allergen-induced trained immunity in tissue resident alveolar macrophages (AMs) and its impact on long-lasting airway hypersensitivity. Here, we utilized flow cytometry and single-cell transcriptomics to analyze immune cell dynamics in murine asthma model, and we compare the differences between allergen-experienced AMs and naïve AMs. Specifically, we introduce and delve into the concept of allergen-induced trained immunity within these particular cells (Trained alveolar macrophages, Tr-AMs). Our findings demonstrated that Tr-AMs preferentially produce pro-eosinophilic chemokines upon subsequent allergen exposure and, therefore, induce exacerbated eosinophilic inflammation in the lung. The induction of Tr-AMs was potentially associated with their interactions with other immune cells, such as natural killer cells, dendritic cells, and Th2 cells. Both IFN-γ and IL-4 are critical for AM activation, we found that their simultaneous action on AMs induced the development of an MHCII⁺ CD206⁺ Tr-AM phenotype, which was specialized in producing pro-eosinophilic chemokines, including CCL24 (eotaxin-2) and CCL5 (RANTES). This study highlights the establishment and roles of Tr-AMs in pro-asthmatic airway hypersensitivity, providing a new understanding of the pathogenesis and recurrence of allergic asthma.