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

Abstract

Behavioral symptoms associated with mood disorders have been intimately linked with immunological and psychological stress. Induction of immune and stress pathways is accompanied by increased tryptophan entry into the Kynurenine (Kyn) Pathway as governed by the rate-limiting enzymes indoleamine/tryptophan 2,3-dioxygenases (DO's: Ido1, Ido2, Tdo2). Indeed, elevated DO expression is associated with inflammation- and stress-related depression symptoms. Here we examined central (brain, astrocyte and microglia) and peripheral (lung, liver and spleen) DO expression in mice treated intraperitoneally with lipopolysaccharide (LPS) and dexamethasone (DEX) to model the response of the Kyn Pathway to inflammation and glucocorticoids. LPS-induced expression of cytokines in peripheral tissues was attenuated by DEX, confirming inflammatory and anti-inflammatory responses, respectively. Increased Kyn levels following LPS and DEX administration verified Kyn Pathway activation. Expression of multiple mRNA isoforms for each DO, which we have shown to be differentially utilized and regulated, were quantified including reference/full-length (FL) and variant (v) transcripts. LPS increased Ido1-FL in brain (∼1000-fold), a response paralleled by increased expression in both astrocytes and microglia. Central Ido1-FL was not changed by DEX; however, LPS-induced Ido1-FL was decreased by DEX in peripheral tissues. In contrast, DEX increased Ido1-v1 expression by astrocytes and microglia, but not peripheral tissues. In comparison, brain Ido2 was minimally induced by LPS or DEX. Uniquely, Ido2-v6 was LPS- and DEX-inducible in astrocytes, suggesting a unique role for astrocytes in response to inflammation and glucocorticoids. Only DEX increased central Tdo2 expression; however, peripheral Tdo2 was upregulated by either LPS or DEX. In summary, specific DO isoforms are increased by LPS and DEX, but LPS-dependent Ido1 and Ido2 induction are attenuated by DEX only in the periphery indicating that elevated DO expression and Kyn production within the brain can occur independent of the periphery. These findings demonstrate a plausible interaction between immune activation and glucocorticoids associated with depression.

Inflammation and post‐traumatic stress disorder

“…Moreover, the increase in proinflammatory cytokines results in reduced production of serotonin by facilitating the breakdown of tryptophan, the primary substrate of serotonin. Glucocorticoids can also play a role in this inflammation‐induced activation of the kynurenine pathway …”

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

“…The target cells are microglia, astrocytes, and other inflammatory cells that are present in the hippocampus and other CNS areas [33]. Once impacted by those cytokines, the cells reduce glutamate reuptake, increase glutamatergic signaling, reduce the capacity to produce serotonin, trigger nociceptive and depressive behavior, and induce cell death (mostly the astrocytes), prolonging the inflammatory effect [13,33,41,53,199].…”

“…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.…”

The Effect of Tryptophan 2,3-Dioxygenase Inhibition on Kynurenine Metabolism and Cognitive Function in the APP23 Mouse Model of Alzheimer’s Disease

“… 7 The production of Kyn is facilitated by the enzymes tryptophan 2,3-dioygenase (TDO) and indoleamine 2,3-dioxygenase (IDO), which are regulated in a tissue-specific manner by pro-inflammatory cytokines and glucocorticoids. 8 , 9 Metabolites of the Kyn pathway— kynurenines —have diverse biological functions including inflammatory control and metabolic regulation. 10 Certain kynurenines have neuroactive properties mainly because they act on NMDA receptors.…”