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

Abstract

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.

Authors:
 [1];  [2];  [3];  [4];  [5];  [1];  [3];  [2];  [2];  [5]; ORCiD logo [4];  [6]
  1. Sandia National Lab. (SNL-CA), Livermore, CA (United States). Dept. of Systems Biology. Biological and Material Sciences
  2. Cornell Univ., Ithaca, NY (United States). Dept. of Chemistry and Chemical Biology
  3. Sandia National Lab. (SNL-CA), Livermore, CA (United States). Dept. of Biotechnology and Bioengineering. Biological and Material Sciences
  4. Los Alamos National Lab. (LANL), Los Alamos, NM (United States)
  5. Univ. of New Mexico, Albuquerque, NM (United States). School of Medicine. Dept. of Pathology
  6. Sandia National Lab. (SNL-CA), Livermore, CA (United States). Biological and Material Sciences
Publication Date:
Research Org.:
Los Alamos National Lab. (LANL), Los Alamos, NM (United States); Sandia National Lab. (SNL-CA), Livermore, CA (United States); Cornell Univ., Ithaca, NY (United States); Univ. of New Mexico, Albuquerque, NM (United States)
Sponsoring Org.:
USDOE Office of Science (SC), Biological and Environmental Research (BER) (SC-23); USDOE National Nuclear Security Administration (NNSA); National Inst. of Health (NIH) (United States); National Institutes of Health (NIH)
OSTI Identifier:
1457302
Alternate Identifier(s):
OSTI ID: 1481886
Report Number(s):
[LA-UR-15-28484; SAND-2018-11800J]
[Journal ID: ISSN 2045-2322]
Grant/Contract Number:  
[AC52-06NA25396; NA0003525; R01DE020891; R01GM111510; P50GM085273; AC04-94AL85000]
Resource Type:
Accepted Manuscript
Journal Name:
Scientific Reports
Additional Journal Information:
[ Journal Volume: 7]; Journal ID: ISSN 2045-2322
Publisher:
Nature Publishing Group
Country of Publication:
United States
Language:
English
Subject:
59 BASIC BIOLOGICAL SCIENCES; computational models; lab-on-a-chip; signal processing

Citation Formats

Harmon, Brooke, Chylek, Lily A., Liu, Yanli, Mitra, Eshan D., Mahajan, Avanika, Saada, Edwin A., Schudel, Benjamin R., Holowka, David A., Baird, Barbara A., Wilson, Bridget S., Hlavacek, William S., and Singh, Anup K. Timescale Separation of Positive and Negative Signaling Creates History-Dependent Responses to IgE Receptor Stimulation. United States: N. p., 2017. Web. doi:10.1038/s41598-017-15568-2.
Harmon, Brooke, Chylek, Lily A., Liu, Yanli, Mitra, Eshan D., Mahajan, Avanika, Saada, Edwin A., Schudel, Benjamin R., Holowka, David A., Baird, Barbara A., Wilson, Bridget S., Hlavacek, William S., & Singh, Anup K. Timescale Separation of Positive and Negative Signaling Creates History-Dependent Responses to IgE Receptor Stimulation. United States. doi:10.1038/s41598-017-15568-2.
Harmon, Brooke, Chylek, Lily A., Liu, Yanli, Mitra, Eshan D., Mahajan, Avanika, Saada, Edwin A., Schudel, Benjamin R., Holowka, David A., Baird, Barbara A., Wilson, Bridget S., Hlavacek, William S., and Singh, Anup K. Tue . "Timescale Separation of Positive and Negative Signaling Creates History-Dependent Responses to IgE Receptor Stimulation". United States. doi:10.1038/s41598-017-15568-2. https://www.osti.gov/servlets/purl/1457302.
@article{osti_1457302,
title = {Timescale Separation of Positive and Negative Signaling Creates History-Dependent Responses to IgE Receptor Stimulation},
author = {Harmon, Brooke and Chylek, Lily A. and Liu, Yanli and Mitra, Eshan D. and Mahajan, Avanika and Saada, Edwin A. and Schudel, Benjamin R. and Holowka, David A. and Baird, Barbara A. and Wilson, Bridget S. and Hlavacek, William S. and Singh, Anup K.},
abstractNote = {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.},
doi = {10.1038/s41598-017-15568-2},
journal = {Scientific Reports},
number = ,
volume = [7],
place = {United States},
year = {2017},
month = {11}
}

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