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 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.
Ng
Gilbert
G
Department of Microbiology and Infectious Diseases, Immunology Research Group, University of Calgary, Calgary, Alberta T2N 4N1, Canada.
Sharma
Karan
K
Ward
Sandra M
SM
Desrosiers
Melanie D
MD
Stephens
Leslie A
LA
Schoel
W Michael
WM
Li
Tonglei
T
Lowell
Clifford A
CA
Ling
Chang-Chun
CC
Amrein
Matthias W
MW
Shi
Yan
Y
D033942:Adaptor Proteins, Vesicular Transport / Q000378:metabolism; D000818:Animals; D002462:Cell Membrane / Q000276:immunology / Q000378:metabolism*; D002784:Cholesterol / Q000378:metabolism*; D003713:Dendritic Cells / Q000201:enzymology / Q000276:immunology* / Q000378:metabolism; D004789:Enzyme Activation; D055785:Gene Knockdown Techniques; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism*; D008213:Lymphocyte Activation; D008563:Membrane Lipids / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D018625:Microscopy, Atomic Force; D053594:Myeloid Differentiation Factor 88 / Q000378:metabolism; D011485:Protein Binding; D011505:Protein-Tyrosine Kinases / Q000378:metabolism*; D015398:Signal Transduction; D000072377:Syk Kinase; D014527:Uric Acid / Q000276:immunology* / Q000378:metabolism
D033942:Adaptor Proteins, Vesicular Transport; D002784:Cholesterol; D047908:Intracellular Signaling Peptides and Proteins; D008563:Membrane Lipids; D053594:Myeloid Differentiation Factor 88; D011505:Protein-Tyrosine Kinases; D000072377:Syk Kinase; D014527:Uric Acid; C507780:Myd88 protein, mouse; C476286:Ticam1 protein, mouse; C000606897:Syk protein, mouse