TNFα mediates stress-induced depression by upregulating indoleamine 2,3-dioxygenase in a mouse model of unpredictable chronic mild stress

Abstract

Depression is often preceded by exposure to stressful life events. Chronic stress causes perturbations in the immune system, and up-regulates production of proinflammatory cytokines, which has been proposed to be associated with the pathogenesis of clinical depression. However, the potential mechanisms by which stress-induced proinflammatory cytokines lead to the development of depression are not well understood. Here, we sought to screen the main proinflammatory cytokines and the potential mechanisms linking inflammation to depression-like behavior during unpredictable, chronic, mild stress (UCMS), in vivo. Mice were allocated into four groups in each separate experiment: saline-control, saline-UCMS, drug-control and drug-UCMS. Development of depression-like behavior was reflected as a reduction in sucrose preference, and increased immobility in both the forced swim and tail suspension tests. The following drugs were administered intraperitoneally: the pan-anti-inflammatory tetracycline derivative, minocycline (30 mg/kg, daily), the tumor necrosis factor (TNF)a monoclonal antibody, infliximab (10 mg/kg, twice weekly), and the indoleamine 2, 3-dioxygenase (IDO) inhibitor, 1-methyltryptophan (1-MT, 10 mg/mouse, daily). Plasma TNFα, IL-1β and IL-18 increased significantly after the four-week UCMS exposure. Pretreatment of mice with minocycline completely blocked any upregulation. Concurrent with development of depression-like behaviors, the concentration of TNFα in plasma and the cerebral cortex increased remarkably. The tryptophan-degrading enzyme IDO was up-regulated in the cortex following UCMS exposure. Treatment of mice with minocycline, infliximab or 1-MT prevented the development of depression-like behaviors. Furthermore, blockade of TNFα inhibited expression of IDO and protected cortical neurons from UCMS-induced damage. These results suggest that TNFα plays a critical role in mediating UCMS-induced depression through up-regulation of IDO and subsequent damage of cortical neurons.

Repeated Social Defeat, Neuroinflammation, and Behavior: Monocytes Carry the Signal

“…preference, and open field exploration (Hinwood, Morandini et al 2012, Kreisel, Frank et al 2014, Liu, Peng et al 2015. In addition, stimulating stress-exposed microglia with an immune challenge reduces social interaction and open field exploration (Wohleb, Fenn et al 2012 which is prevented by minocycline treatment (Chijiwa, Oka et al 2015).…”

Desipramine decreases expression of human and murine indoleamine-2,3-dioxygenases

“…Expression and regulation of the DOs indicate that enhanced DO activity and elevated DO expression are correlated with depression symptomology in both human and rodent models (Brooks et al, 2016b; Capuron et al, 2002; O’Connor et al, 2009a). In preclinical studies, neuroinflammation induced by LPS administration, polyinosinic:polycytidylic acid (pI:C) treatment, peritoneal infection with Mycobacterium bovis or acute/chronic stress culminate in depression-like behaviors such as anhedonia and helplessness/despair (Dantzer and Kelley, 2007; Dantzer et al, 2011; Gibney et al, 2013; Hoyo-Becerra et al, 2014; Liu et al, 2015; Moreau et al, 2008; Wang et al, 2015a). Such pre-clinical models of depression are associated with increased DO expression and/or DO activity, primarily attributed to Ido1 as diminishing DO activity by the administration of Ido1 inhibitors or using Ido1 knockout (KO) mice results in decreased inflammation- and stress-induced depression-like behaviors (Lawson et al, 2013; Liu et al, 2015; O’Connor et al, 2009b; Salazar et al, 2012).…”

“…In preclinical studies, neuroinflammation induced by LPS administration, polyinosinic:polycytidylic acid (pI:C) treatment, peritoneal infection with Mycobacterium bovis or acute/chronic stress culminate in depression-like behaviors such as anhedonia and helplessness/despair (Dantzer and Kelley, 2007; Dantzer et al, 2011; Gibney et al, 2013; Hoyo-Becerra et al, 2014; Liu et al, 2015; Moreau et al, 2008; Wang et al, 2015a). Such pre-clinical models of depression are associated with increased DO expression and/or DO activity, primarily attributed to Ido1 as diminishing DO activity by the administration of Ido1 inhibitors or using Ido1 knockout (KO) mice results in decreased inflammation- and stress-induced depression-like behaviors (Lawson et al, 2013; Liu et al, 2015; O’Connor et al, 2009b; Salazar et al, 2012). Peripheral immune challenges, largely via IFNγ, induce Ido1 and Ido2 (Brooks et al, 2016a; Brooks et al, 2016b; Browne et al, 2012; O’Connor et al, 2009a); whereas, stress hormones induce Tdo2 (Brooks et al, 2016b) in rodent models.…”

M30 Antagonizes Indoleamine 2,3-Dioxygenase Activation and Neurodegeneration Induced by Corticosterone in the Hippocampus

“…In this context, recent studies proposed a significant role of neuroinflammation in the brain of clinically depressed patients [16]. Putatively, it could induce depressive-like behavior in rodents with an activation of inflammatory cytokines-responsive indoleamine 2,3-dioxygenase (IDO-1), which is a key enzyme for the catabolism of tryptophan and serotonin, that could deplete the level of serotonin [17, 18]. In addition, the metabolites of IDO-1 have been reportedly shown to induce neuronal apoptosis and neurodegeneration as a result of IDO-1 activation [19, 20].…”