Knockdown of the Mixed Lineage Kinase Domain-Like Protein (MLKL) Enhances Extramedullary Hematopoiesis to Increase Atherosclerosis

Atherosclerosis is the greatest contributor to death and is characterized by increased blood cholesterol, as well as inflammation in the heart, and is typically recognized as a narrowing of vessels in the heart by a build up of cholesterol-rich plaques. During atherosclerosis, these plaques become unstable and break apart, leading to stroke or heart attack. This in part occurs as the cells of the plaque die, including a mode of cell death known as necroptosis. During necroptosis, through activation of the mixed lineage kinase domain-like protein (MLKL), the cells release their contents and promote inflammation in the heart. We thus hypothesized that inhibiting MLKL would decrease the progression of plaque development during heart disease, however, we found that decreasing MLKL expression in fact increased plaque development. Plaque buildup begins as circulating immune cells home to the heart. These immune cells originate from stem cells in the bone marrow, however during heart disease, these stem cells migrate to the spleen and produce mature immune cells that are released into circulation. This process of stem cell production of mature immune populations in the spleen, however, is incompletely understood. In line with this we found that inhibition of MLKL increased the size of the spleens, as well as the number of the immune stem cells within the spleen but not the bone marrow. Furthermore, decreased MLKL expression in stem cells from the spleen increased their ability to form mature pro-inflammatory immune cells known to contribute to heart disease. These data therefore indicate that MLKL plays a critical role in repressing immune stem cells in the spleen, which therefore limit the production of the mature immune cells that to contribute to heart disease. Further study of MLKL function in controlling immune cells will in turn expand our knowledge of how immune cells are produced with the goal of developing methods to target this in humans to reduce heart disease.