Sex-specific role of CCL5/CCR5 axis in depression and its therapeutic implication

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Summary/Abstract Major depressive disorder (MDD) is a widespread psychological disorder affecting ~7% population in the U.S. The prevalence is even higher in veterans. It was estimated that approximately 30% of Operation Enduring Freedom (OEF) and Operation Iraqi Freedom (OIF) veterans are affected by depression. Sexual dimorphism in depression is well documented. Women and men differ in the prevalence, symptom presentation, and responses to antidepressant treatment. However, the majority of scientific investigations have been predominantly conducted in male models due to experimental limitations. Chronic social defeat stress (CSDS) is one of the best-established models to study depression and has been largely limited to study male depression. Recently, Dr. Russo's lab developed a female CSDS paradigm that consistently produced depression-like behaviors in female mice and has since been adopted in our laboratory. Induction of inflammatory cytokines in the periphery contributes to depression-like behaviors both in humans and in experimental models. Previously, it was found that stress-induced peripheral IL-6 plays an important role in determining stress-susceptibility in male mice. Characterization of peripheral inflammation in female mice following CSDS revealed positive correlation between stress-susceptibility and plasma levels of C- C motif chemokine ligand (CCL5), but not with IL-6. Higher level of CCL5 was also reported in human subjects with MDD and higher levels of peripheral CCL5 in women compared to men, implicating sexual dimorphic interactions between CCL5 expression and depression. Gene expression analysis revealed that CCL5 receptor CCR5 was significantly higher in stress-susceptible female mice in the prefrontal cortex (PFC), a brain region known to play important role in depression, and this increase was not seen in stress-susceptible male mice. Cross-examination with human MDD RNA-seq data showed that in female MDD subjects, the level of CCR5 in the ventromedial PFC was 2.8 fold higher compared to the control subjects and this increase was not seen in male MDD subjects, suggesting conserved responses to stress in human and mouse. CCR5 is a seven-transmembrane G protein-coupled receptor expressed in microglia, astrocytes and neurons in diverse brain regions. Ligand activation of CCR5 has been show to suppress adenylyl cyclase, activate PI3K/AKT and MAPK signaling and alter intracellular Ca2+ mobilization, all of which can influence synaptic function. Based on these observations, we hypothesize that in female mice, defeat stress induces peripheral increase of CCL5 and its interaction with CCR5 in the brain dysregulates synaptic plasticity and promotes stress-susceptibility. We propose to modulate CCL5 in the periphery or manipulate the CCL5/CCR5 signaling, either pharmacologically or genetically in the PFC, and use a battery of neurobehavioral tests, immunological and molecular techniques to test the role of CCL5 and CCR5 in stress-susceptibility in females, and compare the responses to male mice. We will also investigate whether stress-induced neurovascular damage and associated blood brain barrier leakage may facilitate peripheral CCL5 infiltration to the brain. Lastly we will investigate whether oral application of a FDA approved CCR5 antagonist is effective in treating mice with depression-like phenotype and to compare its efficacy with antidepressant fluoxetine. We believe our approach will greatly enhance our understanding of the pathophysiology underlying depression in female and fill the gap in current scientific knowledge on sex-specific periphery and central mechanisms underlying depressive disorder. The treatment intervention proposed in the application will provide immediate bench-to-bed translation and may significantly improve the health and lives of veterans affected by the stress disorders including depression, anxiety disorders and posttraumatic stress disorders (PTSD), particularly relevant to the health and wellbeing of female veterans.