Resolution of inflammation-induced depression requires T lymphocytes and endogenous brain interleukin-10 signaling

Abstract

<p class="first" id="Par1">In humans, depression is often associated with low-grade inflammation, activation of the tryptophan/kynurenine pathway, and mild lymphopenia. Preclinical research confirms that inflammation induces depression-like behavior through activation of the tryptophan/kynurenine pathway. However, the mechanisms governing recovery from depression are unknown. Understanding the pathways leading to resolution of depression will likely lead to identification of novel targets for treatment. We investigated the contribution of T lymphocytes to the resolution of lipopolysaccharide-induced depression-like behavior. Duration of depression-like behavior was markedly prolonged in mice without mature T or B lymphocytes ( <i>Rag1</i> ^−/− mice). This prolonged depression-like behavior was associated with persistent upregulation of the tryptophan-metabolizing enzyme indoleamine-2,3-dioxygenase ( <i>Ido</i>)1 in the prefrontal cortex (PFC). Reconstitution of <i>Rag1</i> ^−/− mice with T lymphocytes normalized resolution of depression-like behavior and expression of <i>Ido1</i> in the PFC. During resolution of inflammation-induced depression-like behavior, T lymphocytes accumulated in the meninges and were required for induction of interleukin (IL)-10 in the meninges and the PFC. Inhibition of IL-10 signaling by nasal administration of neutralizing anti–IL-10 antibody to WT mice led to persistent upregulation of <i>Ido1</i> in the PFC and prolonged depression-like behavior. Conversely, nasal administration of recombinant IL-10 in <i>Rag1</i> ^−/− mice normalized <i>Ido1</i> expression and resolution of depression-like behavior. In conclusion, the present data show for the first time that resolution of inflammation-induced depression is an active process requiring T lymphocytes acting via an IL-10–dependent pathway to decrease <i>Ido1</i> expression in the brain. We propose that targeting the T lymphocyte/IL-10 resolution pathway could represent a novel approach to promote recovery from major depressive disorder. </p>