title: Immunomodulatory Factors Galectin-9 and Interferon-Gamma Synergize to Induce Expression of Rate-Limiting Enzymes of theKynurenine Pathwayin 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 theKynurenine 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 theKynurenine Pathwayhas not been investigated. Thus, we searched for a link between galectins and theKynurenine Pathwayusingin vivoandex vivomodels. Mice were administered LPS and pI:C to determine if galectins (Gal's) were upregulated in the brain followingin vivoinflammatory 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;Kynurenine Pathwayrate-limiting enzymes).In vivo, 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 inducedin vivo, 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 ofKynurenine Pathwayactivation across multiple immune and psychiatric disorders, this synergy provides a new target for therapeutic development.
authors: Neuroscience Program, University of Illinois at Urbana-Champaign, Urbana, IL, USA; Department of Animal Sciences, University of Illinois at Urbana-Champaign, Urbana, IL, USA; Integrative Immunology and Behavior Program, University of Illinois at Urbana-Champaign, Urbana, IL, USA.
authors: Alexandra K
authors: AK
authors: Brooks
authors: Neuroscience Program, University of Illinois at Urbana-Champaign, Urbana, IL, USA; Department of Animal Sciences, University of Illinois at Urbana-Champaign, Urbana, IL, USA; Integrative Immunology and Behavior Program, University of Illinois at Urbana-Champaign, Urbana, IL, USA.
authors: Marcus A
authors: MA
authors: Lawson
authors: Department of Animal Sciences, University of Illinois at Urbana-Champaign, Urbana, IL, USA; Integrative Immunology and Behavior Program, University of Illinois at Urbana-Champaign, Urbana, IL, USA.
authors: Jennifer L
authors: JL
authors: Rytych
authors: Department of Animal Sciences, University of Illinois at Urbana-Champaign, Urbana, IL, USA; Integrative Immunology and Behavior Program, University of Illinois at Urbana-Champaign, Urbana, IL, USA.
authors: Kevin C
authors: KC
authors: Yu
authors: Department of Animal Sciences, University of Illinois at Urbana-Champaign, Urbana, IL, USA; Integrative Immunology and Behavior Program, University of Illinois at Urbana-Champaign, Urbana, IL, USA.
authors: Tiffany M
authors: TM
authors: Janda
authors: Neuroscience Program, University of Illinois at Urbana-Champaign, Urbana, IL, USA; Department of Animal Sciences, University of Illinois at Urbana-Champaign, Urbana, IL, USA; Integrative Immunology and Behavior Program, University of Illinois at Urbana-Champaign, Urbana, IL, USA; Division of Nutritional Science, University of Illinois at Urbana-Champaign, Urbana, IL, USA.
authors: Andrew J
authors: AJ
authors: Steelman
authors: Neuroscience Program, University of Illinois at Urbana-Champaign, Urbana, IL, USA; Department of Animal Sciences, University of Illinois at Urbana-Champaign, Urbana, IL, USA; Integrative Immunology and Behavior Program, University of Illinois at Urbana-Champaign, Urbana, IL, USA; Department of Pathology, University of Illinois at Urbana-Champaign, Urbana, IL, USA.
authors: Robert H
authors: RH
authors: McCusker
keywords: IDO1; IFNγ; cytokines; galectin 9; kynurenine pathway; neuroinflammation