Macrophage Activation by Metabolic and Pathogen Stresses Disorders

Principal Investigator: Mason Freeman

Overview

As the main effector arm of the innate immune system, the macrophage has developed an arsenal of weapons to combat microbial and non-microbial pathogens. The macrophage accomplishes its task, in part, by deploying a group of pattern recognition receptors that recognize common structural motifs present on the surface of the cell walls of microbes. Some of these motifs appear to be present on self tissues undergoing apoptosis; however their recognition does not usually induce the dramatic pro-inflammatory response triggered by microbial contact. Thus, the macrophage has evolved receptor and signal transduction pathways that allow it to distinguish phagocytic activities that need to be accomplished with a minimum of inflammation (e.g., tissue remodeling) from those that must evoke a robust, multicellular inflammatory response (e.g, clearance of microbial pathogens). The overall process of an inflammatory reaction is depicted graphically in Figure 1. With certain stimuli, the process can go awry, either through over-activation in the acute stages (e.g., septic shock following Gram negative bacteremia) or via the failure to resolve over time (e.g., the chronic inflammation of atherosclerosis. One of the central premises of this project is that the macrophage, when engaged by a pro-inflammatory stimulus, has a relatively limited repertoire of responses that it can activate. It is our view that the commonalties of these responses to pathogens, whether microbial or non-microbial, are likely to be substantial and that they account for the similarities in the clinical manifestations of a diverse group of diseases. The over-riding goal of this project is to try to characterize this repertoire of responses in macrophages using high throughput genomic and proteomic technologies.

Specific Aims:

1. To perform comparative gene expression studies assessing the impact of key proteins in inflammatory and stress response pathways, using macrophages taken from wild type and knock-out mice.
2. To explore concordances between murine and human macrophage expression, and to establish baseline profiles revealing the consequences of various sample collection practices.
3. To analyze gene expression in aortas taken from normal and apo E null mice and from coronary arteries of mice following allogeneic heart transplantation.
4. To conduct parallel investigations on the gene expression profiles of human carotid endarterectomy, coronary endarterectomy, and heart transplant specimens, and to establish, if possible, the characteristic gene clustering features of these conditions.

Learn More

To learn more about the Macrophage Activation by Metabolic and Pathogen Stresses Disorders project, visit the Freeman Lab Web Site.