Atypical pericapillary Ly6G⁺Nur77⁺ macrophages initiate type-2 immune responses to allergens in the mouse lung

Abstract

Abstract The mechanisms of airway allergen sensing and type 2 immune response initiation remain poorly understood. Using a mouse house dust mite (HDM)-induced allergic airway model, we identify a population of lung macrophages located close to alveolar capillaries that express Ly6G and the nuclear receptor Nr4a1/Nur77. These atypical Ly6G + Nur77 + macrophages preferentially capture airway-delivered allergens and play an important role in initiating HDM-driven T helper type 2 (Th2) responses. They sense the major HDM allergen, the cysteine protease Der p 1, via protease-activated receptor 2 (PAR2), and their activation and accumulation require both PAR2 and Nr4a1/Nur77. These Ly6G + Nur77 + macrophages regulate the migration of conventional migratory dendritic cells (mDCs) to draining mediastinal lymph nodes (mLNs) through cysteinyl leukotriene (CysLT) production, which enhances mDC migration toward CCL21 for T cell priming. Inhibiting CysLT biosynthesis reduces mDC migration and dampens Th2 allergic responses, highlighting possible therapeutic avenues in type 2 immunity.