Immunomodulatory Factors Galectin-9 and Interferon-Gamma Synergize to Induce Expression of Rate-Limiting Enzymes of the Kynurenine Pathway in the Mouse Hippocampus

• Published in: Frontiers in immunology Vol. 7; p. 422
• Main Authors: Brooks, Alexandra K, Lawson, Marcus A, Rytych, Jennifer L, Yu, Kevin C, Janda, Tiffany M, Steelman, Andrew J, McCusker, Robert H
• Format: Journal Article
• Language: English
• Published: Switzerland Frontiers Media S.A 17.10.2016
• Subjects: galectin 9; IDO1; IFNγ; Immunology; kynurenine pathway; Neuroinflammation; Cytokines; IFNγ; galectin 9; cytokines; kynurenine pathway; neuroinflammation; IDO1
• ISSN: 1664-3224; 1664-3224
• DOI: 10.3389/fimmu.2016.00422

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 . 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 has not been investigated. Thus, we searched for a link between galectins and the using and models. Mice were administered LPS and pI:C to determine if galectins (Gal's) were upregulated in the brain following inflammatory challenges. We then used organotypic hippocampal slice cultures (OHSCs) to determine if Gal's, alone or with inflammatory mediators [interferon-gamma (IFNγ), tumor necrosis factor-alpha (TNFα), 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; rate-limiting enzymes). , hippocampal expression of cytokines (IL-1β, TNFα, and IFNγ), 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 , only IFNγ increased expression of two Ido1 transcripts (Ido1-FL and Ido1-v1) by OHSCs. Although ineffective alone, Gal-9 accentuated IFNγ-induced expression of only Ido1-FL. Similarly, IFNγ induced expression of several Ido2 transcripts (Ido2-v1, Ido2-v3, Ido2-v4, Ido2-v5, and Ido2-v6). Gal-9 accentuated IFNγ-induced expression of only Ido2-v1. Surprisingly, Gal-9 alone, slightly but significantly, induced expression of Tdo2 (Tdo2-v1 and Tdo2-v2, but not Tdo2-FL). 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-v1 and Tdo2-v2) or to enhance IFNγ activity (Ido1-FL and Ido2-v1). Although these novel actions of Gal-9 are described for hippocampus, they have the potential to operate as DO-dependent immunomodulatory processes outside the brain. With the expanding implications of activation across multiple immune and psychiatric disorders, this synergy provides a new target for therapeutic development.