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Updated: Apr 16, 2026
Author Spotlight: Investigating the Pathophysiology of Eosinophilic Esophagitis
Published on: May 10, 2024
Toxicity of eosinophil MBP is repressed by intracellular crystallization and promoted by extracellular aggregation
Alice Soragni1, Shida Yousefi2, Christina Stoeckle2
1UCLA-DOE Institute, HHMI, and Departments of Biological Chemistry and Chemistry and Biochemistry, 611 Charles E. Young Drive, University of California, Los Angeles, Los Angeles, CA 90095-1570, USA; Institute of Pharmacology, University of Bern, Friedbuehlstrasse 49, 3010 Bern, Switzerland; Department of Physical Chemistry, ETH Zurich, Wolfgang-Pauli-Strasse 10, 8093 Zurich, Switzerland.
Abstract:
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.
Insights
Eosinophil major basic protein (MBP-1) is stored as non-toxic nanocrystals within cells. Extracellular release and granule acidification trigger its toxic aggregation, crucial for immunity and disease.
Area of Science:
- Immunology
- Cell Biology
- Biochemistry
Background:
- Eosinophils are key immune cells involved in inflammation and disease.
- Eosinophils contain cytotoxic proteins, such as eosinophil major basic protein (MBP-1), within their granules.
- Mechanisms controlling MBP-1 toxicity during storage and release are not fully understood.
Purpose of the Study:
- To elucidate how eosinophil major basic protein (MBP-1) toxicity is regulated intracellularly and extracellularly.
- To characterize the structure and function of MBP-1 within eosinophil granules.
- To understand the role of MBP-1 aggregation in innate immunity and immunopathology.
Main Methods:
- X-ray-free electron laser (XFEL) characterization of intragranular MBP-1 nanocrystals.
- Analysis of MBP-1 behavior following eosinophil activation and granule acidification.
- Investigation of MBP-1 aggregation states (nanocrystals, extracellular aggregates, amyloid plaques).
Main Results:
- Intragranular MBP-1 is stored as non-toxic nanocrystals, preventing self-toxicity.
- Eosinophil activation and granule acidification trigger toxic MBP-1 aggregation.
- Extracellular MBP-1 aggregates mediate damage to pathogens and host cells.
- Non-toxic amyloid plaques form in pathological conditions, potentially limiting tissue damage.
Conclusions:
- MBP-1 aggregation is a critical mechanism for controlling its toxicity and mediating immune functions.
- Polymorphic self-association pathways of MBP-1 dictate its intra- and extracellular toxicity.
- Understanding MBP-1 aggregation provides insights into eosinophil-mediated immunity and inflammatory diseases.
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