Interactions between inflammatory mediators and corticosteroids regulate transcription of genes within the Kynurenine Pathway in the mouse hippocampus

Abstract

BackgroundIncreased tryptophan metabolism towards the production of kynurenine via indoleamine/tryptophan-2,3-dioxygenases (DOs: Ido1, Ido2, and Tdo2) is strongly associated with the prevalence of major depressive disorder in patients and the induction of depression-like behaviors in animal models. Several studies have suggested that activation of the immune system or elevated corticosteroids drive DO expression; however, mechanisms linking cytokines, corticosteroids, and DOs to psychiatric diseases remain unclear. Various attempts have been made to correlate DO gene expression within the brain to behavior, but disparate results have been obtained. We believe that discrepancies arise as a result of the under-recognized existence of multiple mRNA transcripts for each DO. Unfortunately, there are no reports regarding how the multiple transcripts are distributed or regulated. Here, we used organotypic hippocampal slice cultures (OHSCs) to directly test the ability of inflammatory and stress mediators to differentially regulate DO transcripts.MethodsOHSCs were treated with pro-inflammatory mediators (interferon-gamma (IFNγ), lipopolysaccharide (LPS), and polyinosine-polycytidylic acid (pI:C)) with or without corticosteroids (dexamethasone (Dex: glucocorticoid receptor (GR) agonist), aldosterone (Aldo: mineralocorticoid receptor (MR) agonist), or corticosterone (Cort: GR/MR agonist)).ResultsIFNγ induced Ido1-full length (FL) and Ido1-variant (v) expression, and surprisingly, Dex, Cort, and Aldo interacted with IFNγ to further elevate expression of Ido1, importantly, in a transcript dependent manner. IFNγ, LPS, and pI:C increased expression of Ido2-v1 and Ido2-v3 transcripts, whereas only IFNγ increased expression of Ido2-v2. Overall Ido2 transcripts were relatively unaffected by GR or MR activation. Naïve mouse brain expresses multiple Tdo2 transcripts. Dex and Cort induced expression of only one of the three Tdo2 transcripts (Tdo2-FL) in OHSCs. ConclusionsThese results establish that multiple transcripts for all three DOs are expressed within the mouse hippocampus, under the control of distinct regulatory pathways. These data identify a previously unrecognized interaction between corticosteroid receptor activation and inflammatory signals on DO gene expression, which suggest that corticosteroids act to differentially enhance gene expression of Ido1, Ido2, and Tdo2.

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). 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. Our recent work suggests that stress-inducible factors, glucocorticoids, synergize with IFNγ to further induce the DOs (Brooks et al, 2016a; Brooks et al, 2016b).…”

“…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. Our recent work suggests that stress-inducible factors, glucocorticoids, synergize with IFNγ to further induce the DOs (Brooks et al, 2016a; Brooks et al, 2016b). Thus, the induction of the Kynurenine Pathway following inflammatory and stress-induced stimulation is intimately associated with depression (Capuron et al, 2002; Dantzer and Kelley, 2007; Dantzer et al, 2011; Gibney et al, 2013; Hoyo-Becerra et al, 2014; O’Connor et al, 2009a).…”

“…As such, the Ido1- full length (FL) transcript (comprised of exons 1 ,3,4,5,6,7,8,9,10,11) is poorly expressed in the naïve mouse brain, but is highly inducible by inflammation and stress. In contrast, the Ido1-variant 1 (v1) transcript (comprised of exons 2 ,3,4,5,6,7,8,9,10,11) is well-expressed in the brain, but far less sensitive to inflammatory stimuli (Brooks et al, 2016b). This profile suggests the use of alternate enhancer/promoters to control Ido1 expression in a transcript-dependent manner.…”

Kynurenine pathway metabolism following prenatal KMO inhibition and in Mecp2+/− mice, using liquid chromatography-tandem mass spectrometry

“…The alterations of development are thought to underlie some neurological or psychiatric disorders in the offspring (Brown, 2006, Brown, 2011, Hornig et al., 1999, Meyer and Feldon, 2010). Interferons generated during infection, are potent inducers of indoleamine-2,3-dioxygenase and KMO (Carlin et al., 1989, Alberati-Giani et al., 1996, Silva et al., 2002, Brooks et al., 2016), and corticosteroids produced during stress activate TDO (Green and Curzon, 1975, Green et al., 1976, Nakamura et al., 1987, Young, 1981, Zunszain et al., 2012). These compounds could, therefore, mediate the effects of infection and stress on kynurenine metabolism.…”