Psychological stress is often thought to be immunosuppressive, but it is now known that in some cases stress can enhance certain aspects of the immune response. Despite this knowledge, relatively few studies have focused on stress-induced immunoenhancement. Therefore, the overarching goal of this grant proposal is to identify how stress enhances innate resistance to infectious disease. Social stressors in mice involve physical interactions, making them unique from other types of stressors. The social stressor called social disruption (SDR) has the added characteristic of changing social order and dominance in group-living mice. We have determined that these interactions enhance certain aspects of the immune response. For example, SDR results in the trafficking of CD11b+ myeloid cells from the bone marrow to the spleen, where they are resistant to the suppressive effects of corticosterone and produce significantly higher levels of pro-inflammatory cytokines upon in vitro stimulation with the toll-like receptor (TLR) 4 agonists lipopolysaccharide and lipid A. SDR also increases the capacity of splenic CD11b+ macrophages to kill Escherichia coli in culture. This stress-induced enhancement was also evident in vivo; mice exposed to SDR prior to infection with E. coli cleared the bacteria from the blood and spleen more rapidly than did non-stressed control mice. Because signaling through TLR4 heavily influences the microbicidal activities of macrophages, and because the effects of SDR on CD11b+ cells are dependent upon TLR stimulation, this is an ideal model system to test the hypothesis that social stress enhances resistance to microbial infection by altering TLR4 functioning on CD11b+ cells.
Three specific aims have been developed to: 1) test whether SDR enhances TLR4 expression and/or sensitivity on splenic CD11b+ cells, using microbicidal reactive oxygen intermediates (ROI) and nitric oxide (NO) as outcome variables, 2) examine whether this increased reactivity is dependent upon mitogen activated protein (MAP) kinases p38, JNK, and ERK1/2, which can enhance microbicidal activity 3) examine the importance of SDR-enhanced TLR4 and MAP kinase signaling for clearing a bacterial infection. This interdisciplinary approach will provide valuable insight into the complex host-pathogen relationship during quiescent and stressful periods. Defining the stress-induced cellular changes that enhance immune functioning could stimulate new therapeutic approaches to treating infectious diseases. ? ? ? ?
