Uncovering novel regulators of splenic hematopoiesis during cardiovascular disease

Heart disease is the greatest contributor to death in Western society and is characterized by increased blood cholesterol and inflammation in the heart. Atherosclerosis, a complication of heart disease, is recognized as a narrowing of vessels in the heart by a buildup of cholesterol-rich plaques. Plaque is formed over time by immune cells in the heart taking up cholesterol until it becomes unstable and breaks apart, which can lead to a stroke or heart attack. Normally, immune cells are created from stem cells in the bone marrow; however, during heart disease, these stem cells relocate to the spleen to mature into immune cells before moving to the heart. While we do not fully understand the process and regulation of immune stem cells in the spleen, their contribution to heart disease is evident and becoming increasingly appreciated. The mixed lineage kinase domain-like protein (MLKL) is the committed step of a cell death pathway, which occurs in mature immune cells in the heart after cholesterol uptake. These cells then break open and release their contents, which increases inflammation. My previous work has shown that while reducing MLKL decreases this bad form of cell death, MLKL also promotes the processing of cholesterol to limit plaque development. Furthermore, my recent work has identified MLKL as a unique regulator of the spleen, by preserving the microenvironment that restricts immune cell production from stem cells. My studies as part of this Fellowship will assess how MLKL and other targets work to normally limit immune cell production in the spleen. By first understanding the role of these factors in the spleen, I will not only be able to expand our understanding of how the spleen changes during heart disease, but also identify new ways to limit immune cell production. Ultimately this will allow for the development of better treatments to prevent mortality resulting from heart attack and stroke in patients who already have heart disease.