Timescale Separation of Positive and Negative Signaling Creates History-Dependent Responses to IgE Receptor Stimulation

Sci Rep. 2017 Nov 14;7(1):15586. doi: 10.1038/s41598-017-15568-2.


The high-affinity receptor for IgE expressed on the surface of mast cells and basophils interacts with antigens, via bound IgE antibody, and triggers secretion of inflammatory mediators that contribute to allergic reactions. To understand how past inputs (memory) influence future inflammatory responses in mast cells, a microfluidic device was used to precisely control exposure of cells to alternating stimulatory and non-stimulatory inputs. We determined that the response to subsequent stimulation depends on the interval of signaling quiescence. For shorter intervals of signaling quiescence, the second response is blunted relative to the first response, whereas longer intervals of quiescence induce an enhanced second response. Through an iterative process of computational modeling and experimental tests, we found that these memory-like phenomena arise from a confluence of rapid, short-lived positive signals driven by the protein tyrosine kinase Syk; slow, long-lived negative signals driven by the lipid phosphatase Ship1; and slower degradation of Ship1 co-factors. This work advances our understanding of mast cell signaling and represents a generalizable approach for investigating the dynamics of signaling systems.

MeSH terms

  • Animals
  • Antibodies / immunology
  • Antigens / immunology
  • Basophils / immunology
  • Humans
  • Inflammation / genetics
  • Inflammation / immunology*
  • Inflammation / metabolism
  • Lab-On-A-Chip Devices
  • Mast Cells / immunology*
  • Mast Cells / metabolism
  • Phosphatidylinositol-3,4,5-Trisphosphate 5-Phosphatases / genetics
  • Phosphatidylinositol-3,4,5-Trisphosphate 5-Phosphatases / immunology
  • Receptors, IgE / genetics
  • Receptors, IgE / immunology*
  • Signal Transduction / genetics
  • Signal Transduction / immunology*
  • Syk Kinase / genetics
  • Syk Kinase / immunology


  • Antibodies
  • Antigens
  • Receptors, IgE
  • SYK protein, human
  • Syk Kinase
  • INPP5D protein, human
  • Phosphatidylinositol-3,4,5-Trisphosphate 5-Phosphatases