Ly6G+Nur77+ macrophages initiate the type-2 immune response to allergens in the lung

The mechanisms of allergen sensing and type 2 immune response initiation remain unclear. Using a house dust mite (HDM)-induced allergic airway model, we demonstrated that host detection of protease activity in HDM was crucial for initiating T helper type 2 (Th2) responses. This process was driven by the major allergen Der p 1, a cysteine protease, which was sensed by protease-activated receptor 2 (PAR2) on a novel population of perivascular lung macrophages expressing Ly6G and nuclear receptor Nur77. These macrophages required PAR2 and Nur77 for activation and accumulation and regulated conventional migratory dendritic cell (mDC) migration to draining mediastinal lymph nodes (mLN) via cysteinyl leukotriene (CysLTs) production. CysLTs enhanced CCR7-driven migration of mDCs toward its ligand, CCL21, facilitating arrival to mLNs for T cell priming and expansion. Inhibiting CysLTs biosynthesis reduced mDC migration and dampened Th2 allergic responses, highlighting new therapeutic paths and mechanisms in type 2 immunity. Overall design: This study aims to characterize the early immune cell populations involved in the response to protease allergens in the lung using single-cell RNA sequencing (scRNA-seq). Eight-week-old C57BL/6J mice (species Mus musculus) were treated intranasally with 10 µg of Alexa Fluor 647-labeled cysteine protease papain in a 100 µL volume. Twenty-four hours later, lungs were processed into a single-cell suspension, and papain? cells were isolated using fluorescence-activated cell sorting (FACS). The sorted cells were then subjected to single-cell RNA sequencing (scRNA-seq) to characterize their transcriptional profiles. This dataset provides insights into early immune interactions in the lung following allergen exposure.