Preclinical imaging of immune responses to chronic stress

SUMMARY Psychosocial stress contributes to cardiovascular disease at several stages, including promoting coronary artery disease progression and acutely triggering cardiac events1,2. In this project, we aim to investigate both acute and chronic stress exposure and their immediate and long-term effects on the immune system and atherosclerosis. We will approach these important questions through the development and application of non- invasive imaging methods. Stress activates diverse signaling circuits in the brain, including the hypothalamic-pituitary-adrenal (HPA) axis and the sympathetic nervous system (SNS), which subsequently affect leukocyte distribution and function as well as atherosclerotic plaque inflammation. Specifically, HPA axis activation during acute stress controls lymphocyte and monocyte homing to the bone marrow, while neutrophils are rapidly mobilized from the bone marrow due to motor cortex signaling3. In parallel, SNS activation leads to the production of catecholamines, which induce a long-lasting pro-inflammatory phenotype in monocytes based on metabolic and epigenetic rewiring4,5. SNS activation due to stress has also been directly linked to enhanced atherosclerotic plaque inflammation6,7. During chronic stress exposure, direct sympathetic signaling enhances the proliferation of hematopoietic stem and progenitor cells (HSPCs) in the bone marrow (hematopoiesis), leading to higher numbers of circulating pro-inflammatory neutrophils and monocytes6,8. These cells subsequently extravasate into the arterial wall and enhance plaque inflammation. We hypothesize that stress exposure induces long-term effects on the immune system through the induction of trained immunity and changes in myeloid cell dynamics. In this highly innovative project, we will employ newly developed and established PET imaging methods to probe stress’s effects on the immune system and atherosclerotic plaque inflammation longitudinally, in vivo, and at a whole-body level. In Aim 1, we will focus on metabolic and epigenetic rewiring in hematopoietic organs over the course of stress exposure and after stress withdrawal. Aim 2 evolves around stress-induced alterations in myeloid cell dynamics (cell proliferation, migration, egress, and myeloid cell burden), probed by sophisticated imaging methods. Completing these Aims will help decipher stress’s immediate and long-term impact on the immune system though unique integration of molecular biology and immunology with state-of-the-art translational cardiovascular imaging research.