MODULATION OF MICROGLIA AND CD8+ T LYMPHOCYTE ACTIVATION BY PSYCHOLOGICAL STRESS DURING THE DEVELOPMENT OF STRESS-INDUCED HERPES SIMPLEX VIRUS TYPE-1 ENCEPHALITIS
Open Access
- Author:
- Nair, Aji
- Graduate Program:
- Neuroscience
- Degree:
- Doctor of Philosophy
- Document Type:
- Dissertation
- Date of Defense:
- August 04, 2006
- Committee Members:
- Robert Harold Bonneau, Committee Chair/Co-Chair
Ian Alexander Simpson, Committee Member
Todd Schell, Committee Member
Ralph Norgren, Committee Member
J Kyle Krady, Committee Member - Keywords:
- microglia
central nervous system
CD8+ T cells
glucocorticoids
NMDA receptor
herpes simplex virus
psychological stress - Abstract:
- The immunosuppressive nature of glucocorticoids has been well documented both in vitro and in vivo. This glucocorticoid-mediated immunosuppression has also been observed in immune cells within the central nervous system (CNS). Although microglia function is diminished upon treatment with glucocorticoids in vitro, the impact of glucocorticoids on microglia function in vivo has not been fully investigated. To determine the interaction between glucocorticoids and microglia within the CNS, we used a restraint model of psychological stress to elevate corticosterone levels in mice. Quantification of microglia from stressed mice indicated that four sessions of stress induced the proliferation of microglia. This proliferation was a function of corticosterone-induced activation of the N-methyl-D-aspartate (NMDA) receptor within the CNS since blockade of corticosterone synthesis, the glucocorticoid receptor (GR), or the NMDA receptor each prevented stress-induced increases in microglia number. In addition, the NMDA receptor antagonist MK-801 prevented increases in microglia following exogenous corticosterone administration to non-stressed mice. We conclude that activation of the NMDA receptor and subsequent microglia proliferation is a downstream effect of elevated corticosterone levels. These findings demonstrate that elevated levels of glucocorticoids are able to activate microglia in vivo and suggest that stress is able to induce a pro-inflammatory response within the CNS. Despite these findings, the impact of stress-induced pro-inflammatory responses on CNS inflammation is still not well understood. To determine the effect of corticosterone-induced, NMDA receptor-mediated activation on CNS inflammation, we utilized a murine model of stress-induced herpes simplex virus type-1 (HSV-1) encephalitis (HSE). We have previously demonstrated that psychological stress enhances the development of HSE in mice by delaying the infiltration of HSV-specific CD8+ T cells into the brain. To determine the immune mechanisms by which stress promotes the development of HSE, we examined the role of the GR and the NMDA receptor in the development of HSE. Our findings demonstrate that blockade of either the GR or the NMDA receptor enhances survival following HSV-1 infection in stressed mice to levels similar to non-stressed mice. Subsequent studies determined the effect of GR and NMDA receptor blockade on immune function by specifically examining both microglia and CD8+ T cell activation. Stress inhibited expression of MHC class I by microglia and other brain-derived antigen presenting cells (CD45hi) independent of either the glucocorticoid receptor or the NMDA receptor, indicating that stress-induced suppression of major histocompatability complex (MHC) class I expression in the brain does not affect survival during HSV-1 infection. Blockade of the NMDA receptor, however, diminished HSV-1-induced increases in class I expression by CD45hi cells from non-stressed mice suggesting that blockade of the NMDA receptor may limit CNS inflammation. Also, while CD8+ T cell activation and function in the brain were not affected by stress, the number of CD8+ T cells in the superficial cervical lymph nodes (SCLN) was decreased in stressed mice via GR-mediated mechanisms. These findings indicate that stress-induced hypocellularity is mediated by the GR while NMDA receptor activation is responsible for enhancing CNS inflammation. The combined effects of GR-mediated hypocellularity of the SCLN and NMDA receptor-mediated CNS inflammation during stress promote the development of HSE. Taken together, these studies demonstrate that stress-induced modulation of immune function enhances the susceptibility of the CNS to HSV-1 infection.