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Functional Interactions Between Macrophage and Epithelial Cells

EGFR-regulated genes (microarray analysis using Banjo software).
An example dynamic Bayesian network of early EGFR-regulated genes (microarray analysis using Banjo software). The top 3 genes in the hierarchy are genes of unknown function, showing how our systems biology approaches can suggest new regulatory relationships. Click for a larger version.

Macrophages play a central role in tissue surveillance, and one of their critical functions is to initiate inflammatory signaling that recruits immune cells to localized sites of tissue damage. Macrophages are remarkably effective at cell signaling, considering they make up a small percentage (~3%) of the total tissue cell number, but send their message loud and clear.

The signaling mechanisms underlying macrophage function, though strong and very important, are poorly understood. Systems biologists at Pacific Northwest National Laboratory hypothesize that epithelial cells, which express receptors for many cytokines and chemokines involved in inflammation, function as a filter and amplifier of macrophage inflammatory signals.

We are using a functional module approach to define a macrophage-epithelial model of the inflammation process. While this model will not take into account the many cell types and complexities involved in the inflammatory response, its focus will allow us to characterize early signaling events in a hypothesis-driven manner, using a system that is experimentally and computationally manageable.

Our three-fold, stepwise approach integrates systems biology tools, including microarray, proteomic, and bioinformatic technologies.

  • Develop a dynamic cell process response network for particle-activated macrophages We are examining the genomic and proteomic responses over time of silica-activated macrophages. Our goal is to define a workflow that describes the temporal relationships between major response pathways and links these pathways to specific secreted effectors.
  • Determine the cell response pathways activated in alveolar epithelial cells by paracrine mechanisms and identify candidate regulatory interactions Using data from a related project, Intercellular and Intracellular Communication in the Human Mammary Gland, we will link and compare epithelial response networks to macrophage networks to identify secreted proteins and pathways that couple the input-output properties of the co-culture system.
  • Develop mechanistic models of macrophage and epithelial cell interactions to predict and test amplification and attenuation mechanisms operating in a co-culture environment We will merge the knowledge gained from macrophage and epithelial studies to construct deterministic rate equation-based models that describe the secretory patterns of macrophage and epithelial cell co-cultures. These models will be used to make predictions about key mechanisms for signal amplification and feedback regulation, which will be tested using molecular-level technologies, such as siRNA, gene overexpression, and antibody-based protein inactivation experiments.

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