Toxicity of Eosinophil MBP Is Repressed by Intracellular Crystallization and Promoted by Extracellular Aggregation

Eosinophils are white blood cells that function in innate immunity and participate in the pathogenesis of various inflammatory and neoplastic disorders. Their secretory granules contain four cytotoxic proteins, including the eosinophil major basic protein (MBP-1). How MBP-1 toxicity is controlled within the eosinophil itself and activated upon extracellular release is unknown. Here we show how intragranular MBP-1 nanocrystals restrain toxicity, enabling its safe storage, and characterize them with an X-ray-free electron laser. Following eosinophil activation, MBP-1 toxicity is triggered by granule acidification, followed by extracellular aggregation, which mediates the damage to pathogens and host cells. Larger non-toxic amyloid plaques are also present in tissues of eosinophilic patients in a feedback mechanism that likely limits tissue damage under pathological conditions of MBP-1 oversecretion. Our results suggest that MBP-1 aggregation is important for innate immunity and immunopathology mediated by eosinophils and clarify how its polymorphic self-association pathways regulate toxicity intra- and extracellularly. [Display omitted] •MBP-1 toxicity is restrained via crystallization in eosinophil secretory granules•The nanocrystals are amenable to structural characterization using XFEL radiation•MBP-1 amyloidogenic aggregation mediates toxicity toward pathogens and host cells•Bulky extracellular plaques limit immunopathology in eosinophil-infiltrated organs MBP-1 is a powerful toxin secreted by eosinophils as part of the innate immune response against pathogens that can also cause tissue damage in eosinophilic diseases. Soragni et al. show how MBP-1 crystallization and amyloidogenic aggregation regulate its toxicity toward pathogens and host cells.