Neuroinflammation and comorbid depression: A role for interleukin-1 beta converting enzyme and indoleamine 2,3-dioxygenase

Inflammation is a common component of numerous diseases and considerable evidence has linked components of inflammation with neuropsychiatric disorders. Major depression shares etiologies with inflammatory disease and some postulate that depression is an inflammatory disease. Inflammatory factors such as cytokines have been extensively correlated with depressive disorders in both clinical and experimental models. Whether depression leads to inflammation or inflammation increases the risk of depression remains an open ended debate where substantial evidence supports both sides of this argument. Important when considering the role that inflammation plays in depression, regardless of whether it is causative or resulting from products of inflammation, is that depression and inflammation have been linked. Depression is comorbid with numerous inflammatory diseases including diseases of the central nervous system. Individuals stricken with neurodegenerative diseases such as Alzheimer's, Parkinson's or human immunodeficiency virus (HIV) disease display a higher prevalence of comorbid depression during their life span. Common in these neurodegenerative disorders is inflammation within the central nervous system or neuroinflammation. Neuroinflammation is recognized as an activation of microglia and astrocytes in nervous system tissues that leads to production of inflammatory mediators. Interleukin-1 beta (IL-1beta) is a proinflammatory cytokine that elicits physiological and behavioral disturbances associated with both neuroinflammatory degenerative diseases and mood disorders. IL-1beta requires enzymatic maturation by interleukin-1 beta converting enzyme (ICE) before being released as mature active cytokine. ICE activity is induced predominately during inflammatory events and deletion of ICE has previously been shown to be protective following lipopolysaccharides (LPS) administration. A series of studies were designed to test the hypothesis that ICE is necessary for development of depression-like behaviors in response to neuroinflammation induced by LPS. These studies established that ICE in brain is necessary for depression-like behavior in response to immune stimulation induced by central administration of lipopolysaccharide (LPS). Moreover, these studies established that deletion of ICE prevented the sustained expression of brain cytokine mRNA that corresponded to protection against LPS-induced depression like behavior. The tryptophan degrading enzyme indoleamine 2,3-dioxygenase 1 (IDO1) has also been implicated in neurodegenerative disease and depression. IDO1 activity increases kynurenine concentrations in circulation and brain tissue following LPS administration. Further, IDO1 has been shown to be necessary for the development of systemic inflammation-induced depressionlike behaviors of mice. Increased brain kynurenine however, has not been linked to increased brain-specific IDO1 activity and depression-like behavior. A series of studies were conducted to investigate depression-like behavior and subsequent IDO1 activity of mice following a modest dose of LPS administered directly into brain. LPS increased kynurenine concentration specifically within brain that culminated in depression-like behavior. Genetic deletion of IDO1 or administering a pharmacological inhibitor, 1-methyl tryptophan, into the brain protected mice from LPS-induced depression-like behavior. These effects on behavior indicate that activation of brain IDO1 is necessary to induce depression-like behavior. HIV disease is characterized by the infiltration of infected cells into the brain that results in many of the neurological disturbances observed during disease progression, known as neuroAIDS. Neuroinflammation represents a significant component to many HIV-associated neurological disorders. Further, increased prevalence of comorbid depression is observed with HIV infection. HIV proteins have drawn significant interest for their role in the inflammatory cascades that lead to neurodegenerative components of HIV disease. The HIV transactivator of transcription (Tat) protein is known to initiate an inflammatory response. A series of studies was designed to determine whether acute brain administration of Tat induced neuroinflammation, brain cytokine and IDO1 expression that subsequently induced depression-like behavior. A single injection of Tat induced depression-like behavior that was accompanied by increased brain expression of proinflammatory cytokines and IDO1. Tat also induced mRNA expression of genes associated with activation of microglia and astrocytes. Taken together these findings indicate that Tat in the brain induces neuroinflammation and also induces depression-like behavior demonstrating a potential causative role for Tat in HIV comorbid depression. These studies sought to characterize a role for both ICE and IDO1 in models of neuroinflammation comorbid depression induced by both LPS and HIV Tat protein. It was hypothesized that both of these molecules contribute to the development of neuroinflammation induced depression-like behavior. These findings confirm the hypothesis and establish that ICE and IDO1 represent potential therapeutic targets for alleviating comorbid depression associated with neuroinflammatory disease.