Frontiers in Immunology (Oct 2016)
Immunomodulatory factors galectin-9 and interferon-gamma synergize to induce expression of rate-limiting enzymes of the Kynurenine Pathway in the mouse hippocampus
Abstract
Elevated levels of circulating pro-inflammatory cytokines are associated with symptomology of several psychiatric disorders, notably major depressive disorder. Symptomology has been linked to inflammation/cytokine-dependent induction of the Kynurenine Pathway. Galectins, like pro-inflammatory cytokines, play a role in neuroinflammation and the pathogenesis of several neurological disorders, but without a clearly defined mechanism of action. Their involvement in the Kynurenine Pathway has not been investigated. Thus, we searched for a link between galectins and the Kynurenine Pathway using in vivo and ex vivo models. Mice were administered LPS and pI:C to determine if galectins (Gal's) were upregulated in the brain following in vivo inflammatory challenges. We then used organotypic hippocampal slice cultures (OHSCs) to determine if Gal's, alone or with inflammatory mediators (interferon-gamma (IFNg), tumor necrosis factor-alpha (TNFa), interleukin-1beta (IL-1β), polyinosine-polycytidylic acid (pI:C) and dexamethasone (Dex; synthetic glucocorticoid)), would increase expression of indoleamine/tryptophan-2,3-dioxygenases (DO’s: Ido1, Ido2 and Tdo2; Kynurenine Pathway rate-limiting enzymes). In vivo, hippocampal expression of cytokines (IL-1β, TNFa and IFNg), Gal-3 and Gal-9 along with Ido1 and Ido2 were increased by LPS and pI:C (bacterial and viral mimetics). Of the cytokines induced in vivo, only IFNg increased expression of Ido1 (transcripts: Ido1-FL and Ido1-v1) by OHSCs. Although ineffective alone, Gal-9 interacted with IFNg to further induce expression of Ido1-FL. Similarly, IFNg induced expression of several Ido2 transcripts (Ido2-v1, Ido2-v3, Ido2-v4, Ido2-v5 and Ido2-v6). Gal-9 interacted with IFNg to accentuate expression of only Ido2-v1. Surprisingly, Gal-9 alone, slightly but significantly, induced expression of Tdo2 (Tdo2-v1 and Tdo2-v2). These effects were specific to Gal-9 as Gal-1 and Gal-3 did not alter DO expression. These results are the first to show that brain Gal-9 is increased during LPS- and pI:C-induced neuroinflammation. Increased expression of Gal-9 may be critical for neuroinflammation-dependent induction of DO expression, either acting alone (Tdo2) or to enhance IFNg activity (Ido1/Ido2). Although this novel interaction between Gal-9 and IFNg is described for hippocampus, it has the potential to operate as a DO-dependent immunomodulatory process outside the brain. With the expanding implications of Kynurenine Pathway activation across multiple immune and psychiatric disorders, this interaction provides a new target for therapeutic development.
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