Macrophage-mediated regulation of inflammation and tissue repair

PROJECT SUMMARY Inflammation is required for both pathogen clearance and tissue repair. Mucosal tissues are in continuous contact with the external environment, making these sites highly vulnerable to infection and tissue damage from a variety of sources. Damage can occur as a result of both external insults and the ensuing inflammatory cascade. Therefore, robust responses are required to both dampen inflammation and repair damaged tissue. Epithelial repair is known to occur through local stem and progenitor populations, however, the interplay between the epithelium and immune cells within the local microenvironment is more enigmatic. One such cell type, the macrophage, plays important roles in immune surveillance, repair, and homeostasis across multiple tissues. However, the direct role of macrophages in epithelial regeneration is not well understood. In my laboratory over the next several years, we will interrogate the role of macrophages in regulating inflammatory responses and promoting tissue repair and remodeling. More specifically, we are interested in deciphering macrophage- epithelial cell interactions following viral and chemical damage in mucosal tissues to identify novel regulators of repair. We will use both in vivo damage models and ex vivo organoid systems to: 1) determine how macrophages regulate inflammatory responses to promote host survival and 2) define how macrophages mediate tissue repair through communication with epithelial cells. The long-term goal of my research program is to expand our knowledge surrounding immune cell functions in tissue repair and remodeling in barrier tissues. Our proposed interdisciplinary approaches at the interface between innate immunity and regenerative medicine will bring fresh insight to biological problems at the center of many complex diseases. Understanding the reparative capacity of immune cell populations will allow development of new therapeutic strategies to dampen pathological inflammatory responses, enhance repair following infection and injury, and decrease the pathological tissue remodeling associated with many disease states.