- We’re following up our discovery that the T cell subtype Th17 cells promote susceptibility to depression.
- We identified critical signaling mechanisms by which stress induces an inflammatory response and identified a new potential therapeutic intervention ((+)-naloxone).
- We identified the first specific signaling mechanism by which the gut microbiome releases a molecule (AI-2) to modulate depression sensitivity.
Th17 Cells as Therapeutic Targets for Depression
We discovered that a specific subtype of T cell called Th17 promotes susceptibility to depressive-like behaviors in mice and identified feasible interventions. The project aims to characterize, localize, and identify Th17 cells’ mechanisms of action after stress and test the potential therapeutic impact of targeting Th17 cells to reduce depression vulnerability. We assess this by measuring depression-like behaviors in mice.
This research evolved from the well-established link between inflammation and depression. We reasoned that therapeutically targeting downstream and prolonged outcomes of inflammation may be more feasible than trying to neutralize the multitude of cytokines transiently induced in the stress inflammatory response. Inflammatory cytokines associated with depression drive the production of Th17 cells, and Th17 cells are already known to be toxic to the central nervous system.
In mouse models, we found that Th17 cells can infiltrate the mouse brain parenchyma after stress. These infiltrating cells showed characteristics of pathogenic (CCR6+ and IL-23R+) and follicular (CXCR5+) Th17 cells, and the presence of CCR6 on Th17 cells was required for them to promote depression-like behaviors in mice. However, we still need to identify the mechanisms of action of Th17 cells in depression.
The Microbiota: A Potential Link Between Th17 Cells and Depression
Recent evidence has shown that alterations of the gut microbiota influence responses to stress. Microbiota also influences immune responses — particularly how certain bacteria regulate Th17 cell production.
Our overall hypotheses are that stress that induces depression-like behaviors in mice alters signals generated by certain microflora residents. These signals promote the production of pathogenic Th17 cells, which mediate the induction of depression-like behaviors after stress. The establishment of depression augments changes in the microbiota that facilitate the continued susceptibility to depression, in part through up-regulated production of Th17 cells.
Understanding Stress Susceptibility and Resilience
The immune system’s influences on the brain are poorly understood. Immune cells survey the brain and participate in brain immunity to maintain homeostasis, but immune system-mediated neuroinflammation has been associated with brain damage and diseases. These findings suggest immune system actions on the brain are both beneficial and detrimental.
After stress, peripheral immune cells infiltrate the brain, which is thought to affect mood, cognition, and behaviors. Yet, not everyone experiencing stressful events develop pathologies. Therefore, uncovering the various inflammatory pathways associated with stress might provide novel therapeutic targets.