Regulation of Lymphatic GM-CSF Expression by the E3 Ubiquitin Ligase Cbl-b
Genome-wide association studies as well as lymphatic expression analyses have linked both Cbl-b and GM-CSF to human multiple sclerosis as well as other autoimmune diseases. Both Cbl-b and GM-CSF have been shown to play a prominent role in the development of murine encephalomyelitis; however, no func...
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| Format: | Article |
| Language: | English |
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Frontiers Media S.A.
2018-10-01
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| Series: | Frontiers in Immunology |
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| Online Access: | https://www.frontiersin.org/article/10.3389/fimmu.2018.02311/full |
| _version_ | 1818276395388764160 |
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| author | Sebastian Peer Giuseppe Cappellano Giuseppe Cappellano Natascha Hermann-Kleiter Karin Albrecht-Schgoer Reinhard Hinterleitner Reinhard Hinterleitner Gottfried Baier Thomas Gruber |
| author_facet | Sebastian Peer Giuseppe Cappellano Giuseppe Cappellano Natascha Hermann-Kleiter Karin Albrecht-Schgoer Reinhard Hinterleitner Reinhard Hinterleitner Gottfried Baier Thomas Gruber |
| author_sort | Sebastian Peer |
| collection | DOAJ |
| description | Genome-wide association studies as well as lymphatic expression analyses have linked both Cbl-b and GM-CSF to human multiple sclerosis as well as other autoimmune diseases. Both Cbl-b and GM-CSF have been shown to play a prominent role in the development of murine encephalomyelitis; however, no functional connection between the two has yet been established. In this study, we show that Cblb knockout mice demonstrated significantly exacerbated severity of experimental autoimmune encephalomyelitis (EAE), augmented T cell infiltration into the central nervous system (CNS) and strongly increased production of GM-CSF in T cells in vitro and in vivo.GM-CSF neutralization demonstrated that the increased susceptibility of Cblb−/− mice to EAE was dependent on GM-CSF. Mechanistically, p50 binding to the GM-CSF promoter and the IL-3/GM-CSF enhancer element “CNSa” was strongly increased in nuclear extracts from Cbl-b-deficient T cells. This study suggests that Cbl-b limits autoimmunity by preventing the pathogenic effects of GM-CSF overproduction in T cells. |
| first_indexed | 2024-12-12T22:44:58Z |
| format | Article |
| id | doaj.art-cd602b13e7fa48e99b82131581b2c016 |
| institution | Directory Open Access Journal |
| issn | 1664-3224 |
| language | English |
| last_indexed | 2024-12-12T22:44:58Z |
| publishDate | 2018-10-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Immunology |
| spelling | doaj.art-cd602b13e7fa48e99b82131581b2c0162022-12-22T00:09:14ZengFrontiers Media S.A.Frontiers in Immunology1664-32242018-10-01910.3389/fimmu.2018.02311385223Regulation of Lymphatic GM-CSF Expression by the E3 Ubiquitin Ligase Cbl-bSebastian Peer0Giuseppe Cappellano1Giuseppe Cappellano2Natascha Hermann-Kleiter3Karin Albrecht-Schgoer4Reinhard Hinterleitner5Reinhard Hinterleitner6Gottfried Baier7Thomas Gruber8Division of Translational Cell Genetics, Department for Medical Genetics, Molecular and Clinical Pharmacology, Medical University of Innsbruck, Innsbruck, AustriaDivision of Translational Cell Genetics, Department for Medical Genetics, Molecular and Clinical Pharmacology, Medical University of Innsbruck, Innsbruck, AustriaDepartment of Dermatology, Venereology and Allergology, Medical University of Innsbruck, Innsbruck, AustriaDivision of Translational Cell Genetics, Department for Medical Genetics, Molecular and Clinical Pharmacology, Medical University of Innsbruck, Innsbruck, AustriaDivision of Translational Cell Genetics, Department for Medical Genetics, Molecular and Clinical Pharmacology, Medical University of Innsbruck, Innsbruck, AustriaDivision of Translational Cell Genetics, Department for Medical Genetics, Molecular and Clinical Pharmacology, Medical University of Innsbruck, Innsbruck, AustriaDepartment of Immunology, University of Pittsburgh School of Medicine, Pittsburgh, PA, United StatesDivision of Translational Cell Genetics, Department for Medical Genetics, Molecular and Clinical Pharmacology, Medical University of Innsbruck, Innsbruck, AustriaDivision of Translational Cell Genetics, Department for Medical Genetics, Molecular and Clinical Pharmacology, Medical University of Innsbruck, Innsbruck, AustriaGenome-wide association studies as well as lymphatic expression analyses have linked both Cbl-b and GM-CSF to human multiple sclerosis as well as other autoimmune diseases. Both Cbl-b and GM-CSF have been shown to play a prominent role in the development of murine encephalomyelitis; however, no functional connection between the two has yet been established. In this study, we show that Cblb knockout mice demonstrated significantly exacerbated severity of experimental autoimmune encephalomyelitis (EAE), augmented T cell infiltration into the central nervous system (CNS) and strongly increased production of GM-CSF in T cells in vitro and in vivo.GM-CSF neutralization demonstrated that the increased susceptibility of Cblb−/− mice to EAE was dependent on GM-CSF. Mechanistically, p50 binding to the GM-CSF promoter and the IL-3/GM-CSF enhancer element “CNSa” was strongly increased in nuclear extracts from Cbl-b-deficient T cells. This study suggests that Cbl-b limits autoimmunity by preventing the pathogenic effects of GM-CSF overproduction in T cells.https://www.frontiersin.org/article/10.3389/fimmu.2018.02311/fulladaptive immunitymultiple sclerosisexperimental autoimmune encephalomyelitisCbl-bGM-CSF |
| spellingShingle | Sebastian Peer Giuseppe Cappellano Giuseppe Cappellano Natascha Hermann-Kleiter Karin Albrecht-Schgoer Reinhard Hinterleitner Reinhard Hinterleitner Gottfried Baier Thomas Gruber Regulation of Lymphatic GM-CSF Expression by the E3 Ubiquitin Ligase Cbl-b Frontiers in Immunology adaptive immunity multiple sclerosis experimental autoimmune encephalomyelitis Cbl-b GM-CSF |
| title | Regulation of Lymphatic GM-CSF Expression by the E3 Ubiquitin Ligase Cbl-b |
| title_full | Regulation of Lymphatic GM-CSF Expression by the E3 Ubiquitin Ligase Cbl-b |
| title_fullStr | Regulation of Lymphatic GM-CSF Expression by the E3 Ubiquitin Ligase Cbl-b |
| title_full_unstemmed | Regulation of Lymphatic GM-CSF Expression by the E3 Ubiquitin Ligase Cbl-b |
| title_short | Regulation of Lymphatic GM-CSF Expression by the E3 Ubiquitin Ligase Cbl-b |
| title_sort | regulation of lymphatic gm csf expression by the e3 ubiquitin ligase cbl b |
| topic | adaptive immunity multiple sclerosis experimental autoimmune encephalomyelitis Cbl-b GM-CSF |
| url | https://www.frontiersin.org/article/10.3389/fimmu.2018.02311/full |
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