Abstract
Binding of particulate antigens by antigen-presenting cells is a critical step in immune activation. Previously, we demonstrated that uric acid crystals are potent adjuvants, initiating a robust adaptive immune response. However, the mechanisms of activation are unknown. By using atomic force microscopy as a tool for real-time single-cell activation analysis, we report that uric acid crystals could directly engage cellular membranes, particularly the cholesterol components, with a force substantially stronger than protein-based cellular contacts. Binding of particulate substances activated Syk kinase-dependent signaling in dendritic cells. These observations suggest a mechanism whereby immune cell activation can be triggered by solid structures via membrane lipid alteration without the requirement for specific cell-surface receptors, and a testable hypothesis for crystal-associated arthropathies, inflammation, and adjuvanticity.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Adaptor Proteins, Vesicular Transport / metabolism
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Animals
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Cell Membrane / immunology
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Cell Membrane / metabolism*
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Cholesterol / metabolism*
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Dendritic Cells / enzymology
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Dendritic Cells / immunology*
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Dendritic Cells / metabolism
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Enzyme Activation
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Gene Knockdown Techniques
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Intracellular Signaling Peptides and Proteins / metabolism*
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Lymphocyte Activation
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Membrane Lipids / metabolism*
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Mice
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Mice, Inbred C57BL
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Microscopy, Atomic Force
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Myeloid Differentiation Factor 88 / metabolism
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Protein Binding
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Protein-Tyrosine Kinases / metabolism*
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Signal Transduction
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Syk Kinase
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Uric Acid / immunology*
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Uric Acid / metabolism
Substances
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Adaptor Proteins, Vesicular Transport
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Intracellular Signaling Peptides and Proteins
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Membrane Lipids
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Myd88 protein, mouse
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Myeloid Differentiation Factor 88
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TICAM-1 protein, mouse
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Uric Acid
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Cholesterol
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Protein-Tyrosine Kinases
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Syk Kinase
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Syk protein, mouse