Glial and tissue-specific regulation of Kynurenine Pathway dioxygenases by acute stress of mice

Abstract

Stressors activate the hypothalamic-pituitary-adrenal (HPA) axis and immune system eliciting changes in cognitive function, mood and anxiety. An important link between stress and altered behavior is stimulation of the Kynurenine Pathway which generates neuroactive and immunomodulatory kynurenines. Tryptophan entry into this pathway is controlled by rate-limiting indoleamine/tryptophan 2,3-dioxygenases (DOs: Ido1, Ido2, Tdo2). Although implicated as mediating changes in behavior, detecting stress-induced DO expression has proven inconsistent. Thus, C57BL/6J mice were used to characterize DO expression in brain-regions, astrocytes and microglia to characterize restraint-stress-induced DO expression. Stress increased kynurenine in brain and plasma, demonstrating increased DO activity. Of three Ido1 transcripts, only Ido1-v1 expression was increased by stress and within astrocytes, not microglia, indicating transcript- and glial-specificity. Stress increased Ido1-v1 only in frontal cortex and hypothalamus, indicating brain-region specificity. Of eight Ido2 transcripts, Ido2-v3 expression was increased by stress, again only within astrocytes. Likewise, stress increased Tdo2-FL expression in astrocytes, not microglia. Interestingly, Ido2 and Tdo2 transcripts were not correspondingly induced in Ido1-knockout (Ido1KO) mice, suggesting that Ido1 is necessary for the central DO response to acute stress. Unlike acute inflammatory models resulting in DO induction within microglia, only astrocyte DO expression was increased by acute restraint-stress, defining their unique role during stress-dependent activation of the Kynurenine Pathway.

Neurological and Inflammatory Manifestations in Sjögren’s Syndrome: The Role of the Kynurenine Metabolic Pathway

“…Additionally, to demonstrate the differences in KP activity between the CNS and other parts of the body, systemic treatment with dexamethasone to reduce the inflammation that is induced by lipopolysaccharide (LPS) intraperitoneal injection was shown to promote a decrease in IDO enzymes in peripheral tissues (lung, spleen and liver) but an increase in brain microglial cells and astrocytes [199,208]. Moreover, the use of systemic subcutaneous slow-release corticosteroid pellets in rats increased the levels of NR2 NMDA glutamatergic receptors mRNA in the hippocampus [209].…”

“…Moreover, during chronic inflammation such as in SS, the levels of serotonin in the CNS are diminished by tryptophan consumption throughout the KP. Reversion of the inflammation with corticosteroids in the CNS has been unsuccessful as the inflammation is present in other target organs and leads to the death of microglia, astrocytes, and neurons, mostly in the hippocampus and dorsal ganglion root [199,208,211]. These observations support the possible mechanisms of SS neurological manifestations, in which symptoms of pain and depression (i.e., allodynia, hyperalgesia, and fatigue), manifestations of reduced tear and saliva secretion, and elevated expression of blood markers of inflammation present a dissociation or discrepancy in the affected patients.…”

Kynurenine pathway metabolic balance influences microglia activity: Targeting kynurenine monooxygenase to dampen neuroinflammation

“…However, disruption of neuroendocrine or neuroinflammatory balance, which involves redistribution and activation of microglia within the brain, can shift the metabolic balance toward oxidative metabolism of excitatory and potentially cytotoxic metabolites (Connor et al, 2008). For example, mice exposed to low-level stress exhibit increased expression of IDO1 and TDO (Dugan et al, 2015), and acute stress increases plasma and brain kynurenine (Dostal et al, 2017). Mice lacking the corticosterone-upregulated enzyme tryptophan 2,3-dioxygenase (TDO) fail to develop stress induced depressive-like behaviors (Gibney et al, 2014).…”

Glia- and tissue-specific changes in the Kynurenine Pathway after treatment of mice with lipopolysaccharide and dexamethasone

“…Ido2 isoforms differing in the splicing of an internal exon were transcribed into FL and Δ4 proteins with ~8-fold differences in enzymatic activity. We reported that mRNA isoforms for Ido1, Ido2 and Tdo2 are expressed with both alternate choice of first exons (Class 1 and 2) and alternate splicing of internal exons (Brooks et al, 2017, 2016a, 2016b; Dostal et al, 2017); see supplementary Tables S1–S4 for isoform and qPCR assay descriptions.…”

“…The class 1 reference Ido1 (Ido1-FL) and Ido2 (Ido2-FL) transcripts are basically undetectable in naïve mouse brain and glia, albeit highly inducible (André et al, 2008; Ball et al, 2007; Brooks et al, 2016b; Browne et al, 2012; Croitoru-Lamoury et al, 2011; Dostal et al, 2017; Heisler and O’Connor, 2015; Henry et al, 2009; O’Connor et al, 2009c; Park et al, 2011; Parrott et al, 2016a; Salazar et al, 2012; Wang et al, 2010b). However, the naïve mouse brain has intrinsic Ido activity (Fu et al, 2010; Fujigaki et al, 1998; Lestage et al, 2002; Saito et al, 1992).…”