Transient anxiety and depression-like behaviors are casually associated to depletion of Forkhead box P3 expression in regulatory T cells through inflammasome activation in the brain

Abstract The Forkhead box P3 (Foxp3) is a transcription factor that influences functioning of regulatory T cells (Tregs) which modulates peripheral immune response. Tregs-mediated innate and adaptive immunity are receiving considerable attention for their implication in mechanisms associated with anxiety and depression. Here, we demonstrated that depletion of Foxp3 expression causally promotes transient anxiety and depression-like behaviors associated with inflammasome activation in a Foxp3 conditional knock-out mouse. We found that restoration of Foxp3 expression causally reverses neurobehavioral changes through alteration of innate immune responses as assessed by caspase-1 activity and interleukin-1β release in the hippocampal formation of Foxp3 conditional knock-out mice. Moreover, we found that depletion of Foxp3 expression induces a significant elevation of granulocytes, monocytes, and macrophages in blood, which are associated with transient expression of the matrix metalloprotease-9, and activation of inflammasomes in the brain, as well as neurobehavioral changes. The results suggest that the dynamic regulation of Foxp3-mediated inflammatory responses may be causally associated to anxiety and depression-like behaviors through transient promotion and reversal of innate immunity in the brain. Thus, Foxp3 could be a novel therapeutic target in reversible anxiety and depression.