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An In vitro Model to Study Heterogeneity of Human Macrophage Differentiation and Polarization
Published on: June 12, 2013
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Quantifying dynamic pro-inflammatory gene expression and heterogeneity in single macrophage cells
Beverly Naigles1, Avaneesh V Narla2, Jan Soroczynski3
1Department of Molecular Biology, University of California San Diego, La Jolla, California, USA.
The Journal of Biological Chemistry
|September 9, 2023
Summary
Pro-inflammatory gene expression in macrophages varies with interferon-gamma (IFNγ) stimulus dynamics. IRF1 responds to low IFNγ, while CXCL10/CXCL9 need higher doses, showing significant cell-to-cell variability.
Area of Science:
- Immunology
- Cell Biology
- Systems Biology
Background:
- Macrophages are crucial for immune responses to pathogens.
- Pro-inflammatory gene expression is vital for fighting infection.
- The dynamics (amplitude and duration) of inflammatory stimuli influence cellular responses.
Purpose of the Study:
- To investigate how pro-inflammatory genes (IRF1, CXCL10, CXCL9) respond to dynamic interferon-gamma (IFNγ) stimulation in macrophages.
- To analyze the heterogeneity in gene expression.
- To model the underlying mechanisms of gene expression and heterogeneity.
Main Methods:
- Long-term live cell imaging using microfluidic devices.
- Quantitative analysis of gene expression dynamics.
- Development and application of deterministic and stochastic computational models.
Main Results:
- IRF1 expression is induced by low concentration or short duration IFNγ.
- CXCL10 and CXCL9 require higher concentration or longer duration IFNγ stimulation.
- CXCL10 and CXCL9 exhibit significant cell-to-cell variability, with CXCL10 showing largely stochastic expression.
- Modeling identified a slow chromatin-opening step contributing to CXCL10 heterogeneity.
Conclusions:
- Pro-inflammatory genes within the same pathway exhibit distinct response features to dynamic IFNγ stimulation.
- Upstream signal adaptation and slow chromatin dynamics contribute to heterogeneous gene expression in macrophages.
- Understanding dynamic signaling is key to deciphering immune cell responses.
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