Receptor-Independent, Direct Membrane Binding Leads to Cell-Surface Lipid Sorting and Syk Kinase Activation in Dendritic Cells

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 micros...

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Bibliographic Details
Published in:Immunity (Cambridge, Mass.) Mass.), 2008-11, Vol.29 (5), p.807-818
Main Authors: Ng, Gilbert, Sharma, Karan, Ward, Sandra M., Desrosiers, Melanie D., Stephens, Leslie A., Schoel, W. Michael, Li, Tonglei, Lowell, Clifford A., Ling, Chang-Chun, Amrein, Matthias W., Shi, Yan
Format: Article
Language:English
Subjects:
Adaptor Proteins, Vesicular Transport - metabolism
Animals
Biomedical research
Cell Membrane - immunology
Cell Membrane - metabolism
Cholesterol
Cholesterol - metabolism
Cytokines
Dendritic Cells - enzymology
Dendritic Cells - immunology
Dendritic Cells - metabolism
Enzyme Activation
Gene Knockdown Techniques
Immune system
Intracellular Signaling Peptides and Proteins - metabolism
Ligands
Lipids
Lymphocyte Activation
Medical research
Membrane Lipids - metabolism
Mice
Mice, Inbred C57BL
Microscopy
Microscopy, Atomic Force
MOLIMMUNO
Myeloid Differentiation Factor 88 - metabolism
Protein Binding
Protein-Tyrosine Kinases - metabolism
Signal Transduction
Syk Kinase
Uric Acid - immunology
Uric Acid - metabolism
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Summary: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.
ISSN:1074-7613
1097-4180
DOI:10.1016/j.immuni.2008.09.013