Endothelial Cells Modulate Immune-Brain Signaling After Psychosocial Stress

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Background/Purpose: Stress-related psychiatric disorders, such as depression and anxiety, are among the most common mental health complaints in the community. Anxiety disorders, in particular, affect up to 1 in 3 Americans and severely impact quality of life and productivity. Understanding the biological mechanisms by which stress confers susceptibility to psychiatric disorders is essential in developing interventions to prevent or treat these debilitating conditions. Growing evidence suggests that bidirectional communication between the central nervous system (CNS) and peripheral immune system plays a role in psychiatric disease. For example, a subset of individuals with Major Depressive Disorder (MDD) or Generalized Anxiety Disorder (GAD) have higher plasma inflammatory markers such as CRP and IL-6 and more pro-inflammatory monocytes in circulation. Severely depressed patients who died by suicide had more activated microglia, the innate immune cells of the brain, compared to healthy controls. In our lab, we use a mouse model of psychosocial stress to study the cellular and molecular mechanisms of stress. During social stress, the experimental mice are exposed to a larger, aggressive intruder mouse. The aggressor will attack the subjects to establish dominance in the cage. The loss of social status that the experimental mice experience is a psychosocial stressor. After social stress, mice have increased anxiety-like behaviors as well as increased peripheral and central inflammation, much like humans with psychiatric disease. We have previously shown that social stress causes proliferation and release of pro-inflammatory monocytes from the bone marrow and these monocytes are recruited to the brain, where they interact with the endothelial cells in the brain vasculature. This interaction is essential for the development of anxiety-like behavior after stress. The purpose of the current study was to determine how endothelial cell gene expression changes in the brain after social stress. Research Method: This study utilized the RiboTag mouse, in which ribosomes in specific cell types are tagged with hemagglutinin (HA). The HA tag allows for isolation of those ribosomes and the messenger RNA that are actively being translated to protein. We crossed the RiboTag mouse to a Tie2(endothelial specific)-Cre mouse to generate mice where only ribosomes within endothelial cells would express the HA tag. We exposed the Tie2-Cre x RiboTag mice to six cycles of social stress or left them undisturbed as controls and isolated endothelial-specific mRNA for RNA sequencing. Results: Social stress caused increased translation of genes associated with cell adhesion and trafficking (E-selectin, ICAM-1), innate immunity (S100a9, Ltf), and prostaglandin synthesis and transport (Ptgs2, Slco2a1). These results corroborate our previous findings that social stress increases region-specific expression of cell adhesion molecules. Our findings suggest that the endothelial cells are responding to inflammatory factors and may be contributing to behavioral changes by producing prostaglandins, which many cell types in the brain can respond to. Implications: Brain endothelial cells reside at the interface between the periphery and the CNS. Thus, they are uniquely positioned to transduce signals from peripheral circulating cells to cells within the brain. Endothelial cells are essential for stress-induced anxiety in our mouse model. Targeting endothelial secreted factors or signaling pathways may be a novel axis to prevent or treat psychiatric disease without crossing the blood-brain barrier.


Poster Division: Biological Sciences: 1st Place (The Ohio State University Edward F. Hayes Graduate Research Forum)


neuroscience, neuroimmunology, anxiety, immunology