Immunomodulatory factors galectin-9 and interferon-gamma synergize to induce expression of rate-limiting enzymes of the Kynurenine Pathway in the mouse hippocampus
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 cytoki...
| Main Authors: | , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Frontiers Media S.A.
2016-10-01
|
| Series: | Frontiers in Immunology |
| Subjects: | |
| Online Access: | http://journal.frontiersin.org/Journal/10.3389/fimmu.2016.00422/full |
| _version_ | 1818342726246072320 |
|---|---|
| author | Alexandra K Brooks Alexandra K Brooks Alexandra K Brooks Marcus A Lawson Marcus A Lawson Marcus A Lawson Jennifer L Rytych Jennifer L Rytych Kevin C Yu Kevin C Yu Tiffany M Janda Tiffany M Janda Andrew J Steelman Andrew J Steelman Andrew J Steelman Andrew J Steelman Robert H McCusker Robert H McCusker Robert H McCusker Robert H McCusker |
| author_facet | Alexandra K Brooks Alexandra K Brooks Alexandra K Brooks Marcus A Lawson Marcus A Lawson Marcus A Lawson Jennifer L Rytych Jennifer L Rytych Kevin C Yu Kevin C Yu Tiffany M Janda Tiffany M Janda Andrew J Steelman Andrew J Steelman Andrew J Steelman Andrew J Steelman Robert H McCusker Robert H McCusker Robert H McCusker Robert H McCusker |
| author_sort | Alexandra K Brooks |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-12-13T16:19:16Z |
| format | Article |
| id | doaj.art-e620107f2afb4c94a02034380d2bcf0f |
| institution | Directory Open Access Journal |
| issn | 1664-3224 |
| language | English |
| last_indexed | 2024-12-13T16:19:16Z |
| publishDate | 2016-10-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Immunology |
| spelling | doaj.art-e620107f2afb4c94a02034380d2bcf0f2022-12-21T23:38:45ZengFrontiers Media S.A.Frontiers in Immunology1664-32242016-10-01710.3389/fimmu.2016.00422221771Immunomodulatory factors galectin-9 and interferon-gamma synergize to induce expression of rate-limiting enzymes of the Kynurenine Pathway in the mouse hippocampusAlexandra K Brooks0Alexandra K Brooks1Alexandra K Brooks2Marcus A Lawson3Marcus A Lawson4Marcus A Lawson5Jennifer L Rytych6Jennifer L Rytych7Kevin C Yu8Kevin C Yu9Tiffany M Janda10Tiffany M Janda11Andrew J Steelman12Andrew J Steelman13Andrew J Steelman14Andrew J Steelman15Robert H McCusker16Robert H McCusker17Robert H McCusker18Robert H McCusker19University of Illinois at Urbana-ChampaignUniversity of Illinois at Urbana-ChampaignUniversity of Illinois at Urbana-ChampaignUniversity of Illinois at Urbana-ChampaignUniversity of Illinois at Urbana-ChampaignUniversity of Illinois at Urbana-ChampaignUniversity of Illinois at Urbana-ChampaignUniversity of Illinois at Urbana-ChampaignUniversity of Illinois at Urbana-ChampaignUniversity of Illinois at Urbana-ChampaignUniversity of Illinois at Urbana-ChampaignUniversity of Illinois at Urbana-ChampaignUniversity of Illinois at Urbana-ChampaignUniversity of Illinois at Urbana-ChampaignUniversity of Illinois at Urbana-ChampaignUniversity of Illinois at Urbana-ChampaignUniversity of Illinois at Urbana-ChampaignUniversity of Illinois at Urbana-ChampaignUniversity of Illinois at Urbana-ChampaignUniversity of Illinois at Urbana-ChampaignElevated 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.http://journal.frontiersin.org/Journal/10.3389/fimmu.2016.00422/fullIFNγIDO1kynurenine pathwayNeuroinflammation; Cytokinesgalectin 9 |
| spellingShingle | Alexandra K Brooks Alexandra K Brooks Alexandra K Brooks Marcus A Lawson Marcus A Lawson Marcus A Lawson Jennifer L Rytych Jennifer L Rytych Kevin C Yu Kevin C Yu Tiffany M Janda Tiffany M Janda Andrew J Steelman Andrew J Steelman Andrew J Steelman Andrew J Steelman Robert H McCusker Robert H McCusker Robert H McCusker Robert H McCusker Immunomodulatory factors galectin-9 and interferon-gamma synergize to induce expression of rate-limiting enzymes of the Kynurenine Pathway in the mouse hippocampus Frontiers in Immunology IFNγ IDO1 kynurenine pathway Neuroinflammation; Cytokines galectin 9 |
| title | Immunomodulatory factors galectin-9 and interferon-gamma synergize to induce expression of rate-limiting enzymes of the Kynurenine Pathway in the mouse hippocampus |
| title_full | Immunomodulatory factors galectin-9 and interferon-gamma synergize to induce expression of rate-limiting enzymes of the Kynurenine Pathway in the mouse hippocampus |
| title_fullStr | Immunomodulatory factors galectin-9 and interferon-gamma synergize to induce expression of rate-limiting enzymes of the Kynurenine Pathway in the mouse hippocampus |
| title_full_unstemmed | Immunomodulatory factors galectin-9 and interferon-gamma synergize to induce expression of rate-limiting enzymes of the Kynurenine Pathway in the mouse hippocampus |
| title_short | Immunomodulatory factors galectin-9 and interferon-gamma synergize to induce expression of rate-limiting enzymes of the Kynurenine Pathway in the mouse hippocampus |
| title_sort | immunomodulatory factors galectin 9 and interferon gamma synergize to induce expression of rate limiting enzymes of the kynurenine pathway in the mouse hippocampus |
| topic | IFNγ IDO1 kynurenine pathway Neuroinflammation; Cytokines galectin 9 |
| url | http://journal.frontiersin.org/Journal/10.3389/fimmu.2016.00422/full |
| work_keys_str_mv | AT alexandrakbrooks immunomodulatoryfactorsgalectin9andinterferongammasynergizetoinduceexpressionofratelimitingenzymesofthekynureninepathwayinthemousehippocampus AT alexandrakbrooks immunomodulatoryfactorsgalectin9andinterferongammasynergizetoinduceexpressionofratelimitingenzymesofthekynureninepathwayinthemousehippocampus AT alexandrakbrooks immunomodulatoryfactorsgalectin9andinterferongammasynergizetoinduceexpressionofratelimitingenzymesofthekynureninepathwayinthemousehippocampus AT marcusalawson immunomodulatoryfactorsgalectin9andinterferongammasynergizetoinduceexpressionofratelimitingenzymesofthekynureninepathwayinthemousehippocampus AT marcusalawson immunomodulatoryfactorsgalectin9andinterferongammasynergizetoinduceexpressionofratelimitingenzymesofthekynureninepathwayinthemousehippocampus AT marcusalawson immunomodulatoryfactorsgalectin9andinterferongammasynergizetoinduceexpressionofratelimitingenzymesofthekynureninepathwayinthemousehippocampus AT jenniferlrytych immunomodulatoryfactorsgalectin9andinterferongammasynergizetoinduceexpressionofratelimitingenzymesofthekynureninepathwayinthemousehippocampus AT jenniferlrytych immunomodulatoryfactorsgalectin9andinterferongammasynergizetoinduceexpressionofratelimitingenzymesofthekynureninepathwayinthemousehippocampus AT kevincyu immunomodulatoryfactorsgalectin9andinterferongammasynergizetoinduceexpressionofratelimitingenzymesofthekynureninepathwayinthemousehippocampus AT kevincyu immunomodulatoryfactorsgalectin9andinterferongammasynergizetoinduceexpressionofratelimitingenzymesofthekynureninepathwayinthemousehippocampus AT tiffanymjanda immunomodulatoryfactorsgalectin9andinterferongammasynergizetoinduceexpressionofratelimitingenzymesofthekynureninepathwayinthemousehippocampus AT tiffanymjanda immunomodulatoryfactorsgalectin9andinterferongammasynergizetoinduceexpressionofratelimitingenzymesofthekynureninepathwayinthemousehippocampus AT andrewjsteelman immunomodulatoryfactorsgalectin9andinterferongammasynergizetoinduceexpressionofratelimitingenzymesofthekynureninepathwayinthemousehippocampus AT andrewjsteelman immunomodulatoryfactorsgalectin9andinterferongammasynergizetoinduceexpressionofratelimitingenzymesofthekynureninepathwayinthemousehippocampus AT andrewjsteelman immunomodulatoryfactorsgalectin9andinterferongammasynergizetoinduceexpressionofratelimitingenzymesofthekynureninepathwayinthemousehippocampus AT andrewjsteelman immunomodulatoryfactorsgalectin9andinterferongammasynergizetoinduceexpressionofratelimitingenzymesofthekynureninepathwayinthemousehippocampus AT roberthmccusker immunomodulatoryfactorsgalectin9andinterferongammasynergizetoinduceexpressionofratelimitingenzymesofthekynureninepathwayinthemousehippocampus AT roberthmccusker immunomodulatoryfactorsgalectin9andinterferongammasynergizetoinduceexpressionofratelimitingenzymesofthekynureninepathwayinthemousehippocampus AT roberthmccusker immunomodulatoryfactorsgalectin9andinterferongammasynergizetoinduceexpressionofratelimitingenzymesofthekynureninepathwayinthemousehippocampus AT roberthmccusker immunomodulatoryfactorsgalectin9andinterferongammasynergizetoinduceexpressionofratelimitingenzymesofthekynureninepathwayinthemousehippocampus |