Macrophage-Stromal Cell Interactions in Tissue Homeostasis and Fibrosis

Ruslan Medzhitov, PhD
Yale University

Project Summary:

One of the hallmarks of scleroderma is fibrosis: the buildup of scar tissue that leads to thickening of the skin and, in extreme cases, causes the lungs and other organs to stiffen. That stiffening is responsible for much of the mortality caused by scleroderma. This scar tissue is made up of dense extracellular matrix (the proteins that form the normal scaffolding of any organ) that in scleroderma, is produced excessively. Fibroblasts are the main producers of extracellular matrix, but it is not known how that production is controlled. How is the extracellular matrix monitored to make sure that it does not go awry? We hypothesized that macrophages, immune cells that regulate other conditions within tissues, monitor the extracellular matrix to keep it in check.

We have shown that macrophages can sense changes in the state of the extracellular matrix, and we have early evidence that they use that information to control the production of extracellular matrix by fibroblasts. We are working to determine whether these control mechanisms are broken in scleroderma, leading to excessive production of extracellular matrix and the formation of scar tissue that causes suffering for scleroderma patients. Our goal is to determine, in detail, how macrophages monitor the extracellular matrix and control fibroblast behavior, and what part of this circuit goes awry in scleroderma, so that we can help develop effective treatments that target that pathway.

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