Today,330 million people suffer from asthmaworldwide,which often is a lifelongdisease with daily symptoms. A subgroup of patients has relentless chronic diseasewithfixed airwayobstructionno longer amenable to current therapies. These patients often carry mucus plugs in their airways that contain Charcot-Leyden crystals (CLCs), made up of the eosinophil-derived protein galectin-10. In mice that do not encodegalectin-10, the chitinase-like proteins Ym1 and Ym2 are also commonly observed to form similar crystals in models of asthma. However, whether these crystals are disease-drivers or merely markers of type 2 inflammation is unknown. We hypothesize that crystal formation enforces key aspects of type 2 immunity in the lung-processes that recapitulate lung development but also coincide with inflammatory and pathological tissue-remodeling and fibrosis as seen in severe asthma. To address these questions, this application combines mechanistic studies innovelgenetic mouse models with state-of-the-art immunologicaltools to track Ym1/Ym2 functions and the impact of their crystallinestate during normal physiology and asthma pathology. In vitro cell culture models will help to recapitulate essential structural, functional and immunological aspects of this form of crystallopathy. Finally, two models of early life environmental exposurewill answer whether these crystal forming proteins link early life exposuretopathologic tissue remodeling and asthma development. Combining murine modeling with a proof-of-concept study of human tissues exposed to CLCs, we aim to identify druggable pathways associated with crystal-driven excessive inflammationto benefit individuals with severe allergic airway inflammation.