Abstract
BackgroundTransient stimulation of the innate immune system by an intraperitoneal injection of lipopolysaccharide (LPS) activates peripheral and central expression of the tryptophan degrading enzyme indoleamine 2,3 dioxygenase (IDO) which mediates depressive-like behavior. It is unknown whether direct activation of the brain with LPS is sufficient to activate IDO and induce depressive-like behavior.MethodsSickness and depressive-like behavior in C57BL/6J mice were assessed by social exploration and the forced swim test, respectively. Expression of cytokines and IDO mRNA was measured by real-time RT-PCR and cytokine protein was measured by enzyme-linked immunosorbent assays (ELISAs). Enzymatic activity of IDO was estimated as the amount of kynurenine produced from tryptophan as determined by high pressure liquid chromatography (HPLC) with electrochemical detection.ResultsIntracerebroventricular (i.c.v.) administration of LPS (100 ng) increased steady-state transcripts of TNFα, IL-6 and the inducible isoform of nitric oxide synthase (iNOS) in the hippocampus in the absence of any change in IFNγ mRNA. LPS also increased IDO expression and induced depressive-like behavior, as measured by increased duration of immobility in the forced swim test. The regulation of IDO expression was investigated using in situ organotypic hippocampal slice cultures (OHSCs) derived from brains of newborn C57BL/6J mice. In accordance with the in vivo data, addition of LPS (10 ng/ml) to the medium of OHSCs induced steady-state expression of mRNA transcripts for IDO that peaked at 6 h and translated into increased IDO enzymatic activity within 8 h post-LPS. This activation of IDO by direct application of LPS was preceded by synthesis and secretion of TNFα and IL-6 protein and activation of iNOS while IFNγ expression was undetectable.ConclusionThese data establish that activation of the innate immune system in the brain is sufficient to activate IDO and induce depressive-like behavior in the absence of detectable IFNγ. Targeting IDO itself may provide a novel therapy for inflammation-associated depression.
Highlights
Transient stimulation of the innate immune system by an intraperitoneal injection of lipopolysaccharide (LPS) activates peripheral and central expression of the tryptophan degrading enzyme indoleamine 2,3 dioxygenase (IDO) which mediates depressive-like behavior
Using organotypic hippocampal slice cultures we further demonstrate that this brain area responds to LPS by increased expression of IDO and cytokines, followed by activation of IDO
Central LPS challenge induces an episode of sickness behavior followed by depressive-like behavior Peripheral LPS injection causes depressive-like behavior at 24 h in the absence of sickness response [14,21], so we sought to determine if similar behavioral changes could be induced by centrally administered LPS at a dose (100 ng) that we previously established to induce sickness behavior in both CD1 [41] and C57BL/6J [42,43] mice
Summary
Transient stimulation of the innate immune system by an intraperitoneal injection of lipopolysaccharide (LPS) activates peripheral and central expression of the tryptophan degrading enzyme indoleamine 2,3 dioxygenase (IDO) which mediates depressive-like behavior. It is unknown whether direct activation of the brain with LPS is sufficient to activate IDO and induce depressive-like behavior. Clinical and animal studies implicate systemic inflammation in the pathogenesis of major depressive disorders by activating immune-to-brain communication pathways [1,2,3,4,5]. Inflammation-induced depression is associated with activation of the tryptophan degrading enzyme indoleamine 2,3 dioxygenase (IDO) in both the brain and periphery. Kynurenine can be further degraded into a number of neuroactive metabolites that act as agonists or antagonists of the NMDA receptor that can impact on glutamatergic neurotransmission [18,19,20]
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