Dissecting Immune-Stromal Interactions to Discover Novel Strategy to Modulate Inflammation

Key Words: Macrophage, Fibroblast, Cell-cell interaction,  Growth factor

Inflammation is associated with many pediatric diseases. A proper inflammatory response helps remove frequently encountered bacteria and viruses. However, an inflammatory response in excess causes tissue damage, which can lead to organ dysfunction or even life-threatening disease. Current treatment for pediatric inflammatory disorders, like inflammatory bowel diseases, primarily relies on immune suppressants. Such broad-impact treatments increase both the risk of developmental abnormality as well as susceptibility of serious infections. Understanding how the inflammatory response is regulated quantitatively may inspire the development of new treatments that precisely and specifically normalizes excessive inflammation. To this end, we are interested in studying how macrophages and fibroblasts, two universal cell types in mammalian tissues, collaborate to regulate inflammatory responses.

These cell types are both known to be relevant in the development of different inflammatory disorders, and are often seen interacting and influencing the functions of the other. In particularly, their communication could predict the outcome of pediatric inflammatory bowel diseases. In this project, we will test our hypothesis that targeting the interactions between macrophages and fibroblasts may provide a new way to specifically modulate the inflammatory response. We have reconstituted an in vitro system that allows us to both directly study the interactions between macrophages and fibroblasts, and perturb them in an accessible way to examine quantitative impacts on inflammatory response. In the proposed work, we aim to discover specific genes or proteins that are responsible for building the direct interactions between macrophages and fibroblasts. We will investigate whether targeting these identified genes or proteins could alleviate inflammation. We will also tackle the questions of why and how these two cell types are often associated with each other in order to discover new ways to control them. Our long-term goal is to leverage the mechanisms we will discover here to prevent excessive or prolonged immune response in children with inflammatory bowel diseases or other inflammatory disorders, without shutting down immune system completely.