Macrophage-Stromal Cell Interactions in Tissue Homeostasis and Fibrosis

Ruslan Medzhitov, PhD
Yale University
Howard Hughes Medical Institute

Project Overview

Dr. Medzhitov: 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 the mechanical properties of the extracellular matrix, such as stiffness, and generate signals to control the production and remodeling of extracellular matrix by fibroblasts. We also found that fibroblasts monitor tissue properties to determine the optimal cell density. 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 and fibroblasts monitor the extracellular matrix and control each other behavior, and what part of this circuit goes awry in scleroderma, so that we can help develop effective treatments that target that pathway.

How this work will impact patients

Our philosophy is that every disease is an abnormal version of some biological process and understanding the normal counterpart of disease is essential for the development of cures. Our work addresses these basic biological questions with the aim of identifying the key dysregulated steps so that they can be targeted with new therapeutics.

Role of the Scleroderma Research Foundation

SRF has been instrumental in shaping and focusing my interest in scleroderma research. The annual SRF Workshop is one of my favorite scientific meetings. It provides invaluable opportunities for exchange of ideas and for fostering new collaborations. It has a unique atmosphere of scholarship and shared mission.

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