Grant: Project Grant

Chronic inflammation and fibrosis or scarring are the first triggers of cancer in the liver. Liver fibrosis occurs in response to injury like inflammation due to infection or fatty liver disease where high levels of collagen deposits in the liver leading to stiffness or fibrosis and gradual loss of liver function. The immune system, specifically different subsets of white blood cells produce immune mediators (cytokines) that may increase or decrease the inflammation in the liver and the progression of liver fibrosis. We and other groups have identified a cytokine known as IL17 as a key accelerator of liver fibrosis. We have also identified a subset of white blood cells known as "neutrophils" that produce IL17 and that are increased in advanced fibrosis. In this proposal we are interested in understanding how these neutrophils go to the liver during different types of injury and whether different subsets or types of neutrophils can have different functions or play different roles during early versus late stages of liver injury and fibrosis. We would also like to know where these neutrophils are located in the injured liver and how they interact with the different liver cells. Finally, we would like to see if blocking the activity of these neutrophils and/or IL17 can stop or delay liver fibrosis. To achieve these goals, we will use a combination of imaging techniques and assays to examine these cells in liver tissues from patients at different fibrosis stages as well as mice. We will also use genetically modified mice where cells that produce IL17 at any time during their life will become permanently fluorescent. This will allow us to monitor how these cells travel or change their function in the liver at different stages of liver injury. We will also block the action of IL17 or neutrophils to monitor how this influences fibrosis. The results obtained will guide the development of new treatments to stop liver fibrosis and prevent cancer.