Inhibition of Glycolysis Reduces Disease Severity in an Autoimmune Model of Rheumatoid Arthritis
The K/BxN mouse is a spontaneous model of arthritis driven by T cell receptor transgenic CD4+ T cells from the KRN strain that are activated by glucose-6-phosphate isomerase (GPI) peptides presented by the H-2g7 allele from the NOD strain. It is a model of autoimmune seropositive arthritis because t...
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Frontiers Media S.A.
2018-09-01
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| Online Access: | https://www.frontiersin.org/article/10.3389/fimmu.2018.01973/full |
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| author | Georges Abboud Seung-Chul Choi Nathalie Kanda Leilani Zeumer-Spataro Derry C. Roopenian Laurence Morel |
| author_facet | Georges Abboud Seung-Chul Choi Nathalie Kanda Leilani Zeumer-Spataro Derry C. Roopenian Laurence Morel |
| author_sort | Georges Abboud |
| collection | DOAJ |
| description | The K/BxN mouse is a spontaneous model of arthritis driven by T cell receptor transgenic CD4+ T cells from the KRN strain that are activated by glucose-6-phosphate isomerase (GPI) peptides presented by the H-2g7 allele from the NOD strain. It is a model of autoimmune seropositive arthritis because the production of anti-GPI IgG is necessary and sufficient for joint pathology. The production of high levels of anti-GPI IgG requires on the expansion of CD4+ follicular helper T (Tfh) cells. The metabolic requirements of this expansion have never been characterized. Based on the therapeutic effects of the combination of metformin and 2-deoxyglucose (2DG) in lupus models that normalized the expansion of effector CD4+ T cells. We showed that the CD4+ T cells and to a lesser extent, the B cells from K/BxN mice are more metabolically active than the KRN controls. Accordingly, preventive inhibition of glycolysis with 2DG significantly reduced joint inflammation and the activation of both adaptive and innate immune cells, as well as the production of pathogenic autoantibodies. However, contrary to the lupus-prone mice, the addition of metformin had little beneficial effect, suggesting that glycolysis is the major driver of immune activation in this model. We propose that K/BxN mice are another model in which autoreactive Tfh cells are highly glycolytic and that their function can be limited by inhibiting glucose metabolism. |
| first_indexed | 2024-12-23T14:48:32Z |
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| institution | Directory Open Access Journal |
| issn | 1664-3224 |
| language | English |
| last_indexed | 2024-12-23T14:48:32Z |
| publishDate | 2018-09-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Immunology |
| spelling | doaj.art-501e311affa74ece8b53b2a9f05669592022-12-21T17:43:02ZengFrontiers Media S.A.Frontiers in Immunology1664-32242018-09-01910.3389/fimmu.2018.01973415659Inhibition of Glycolysis Reduces Disease Severity in an Autoimmune Model of Rheumatoid ArthritisGeorges Abboud0Seung-Chul Choi1Nathalie Kanda2Leilani Zeumer-Spataro3Derry C. Roopenian4Laurence Morel5Immunology, and Laboratory Medicine, Department of Pathology, University of Florida, Gainesville, FL, United StatesImmunology, and Laboratory Medicine, Department of Pathology, University of Florida, Gainesville, FL, United StatesImmunology, and Laboratory Medicine, Department of Pathology, University of Florida, Gainesville, FL, United StatesImmunology, and Laboratory Medicine, Department of Pathology, University of Florida, Gainesville, FL, United StatesThe Jackson Laboratory, Bar Harbor, ME, United StatesImmunology, and Laboratory Medicine, Department of Pathology, University of Florida, Gainesville, FL, United StatesThe K/BxN mouse is a spontaneous model of arthritis driven by T cell receptor transgenic CD4+ T cells from the KRN strain that are activated by glucose-6-phosphate isomerase (GPI) peptides presented by the H-2g7 allele from the NOD strain. It is a model of autoimmune seropositive arthritis because the production of anti-GPI IgG is necessary and sufficient for joint pathology. The production of high levels of anti-GPI IgG requires on the expansion of CD4+ follicular helper T (Tfh) cells. The metabolic requirements of this expansion have never been characterized. Based on the therapeutic effects of the combination of metformin and 2-deoxyglucose (2DG) in lupus models that normalized the expansion of effector CD4+ T cells. We showed that the CD4+ T cells and to a lesser extent, the B cells from K/BxN mice are more metabolically active than the KRN controls. Accordingly, preventive inhibition of glycolysis with 2DG significantly reduced joint inflammation and the activation of both adaptive and innate immune cells, as well as the production of pathogenic autoantibodies. However, contrary to the lupus-prone mice, the addition of metformin had little beneficial effect, suggesting that glycolysis is the major driver of immune activation in this model. We propose that K/BxN mice are another model in which autoreactive Tfh cells are highly glycolytic and that their function can be limited by inhibiting glucose metabolism.https://www.frontiersin.org/article/10.3389/fimmu.2018.01973/fullarthritismousefollicular helper T cellsglycolysismetabolism |
| spellingShingle | Georges Abboud Seung-Chul Choi Nathalie Kanda Leilani Zeumer-Spataro Derry C. Roopenian Laurence Morel Inhibition of Glycolysis Reduces Disease Severity in an Autoimmune Model of Rheumatoid Arthritis Frontiers in Immunology arthritis mouse follicular helper T cells glycolysis metabolism |
| title | Inhibition of Glycolysis Reduces Disease Severity in an Autoimmune Model of Rheumatoid Arthritis |
| title_full | Inhibition of Glycolysis Reduces Disease Severity in an Autoimmune Model of Rheumatoid Arthritis |
| title_fullStr | Inhibition of Glycolysis Reduces Disease Severity in an Autoimmune Model of Rheumatoid Arthritis |
| title_full_unstemmed | Inhibition of Glycolysis Reduces Disease Severity in an Autoimmune Model of Rheumatoid Arthritis |
| title_short | Inhibition of Glycolysis Reduces Disease Severity in an Autoimmune Model of Rheumatoid Arthritis |
| title_sort | inhibition of glycolysis reduces disease severity in an autoimmune model of rheumatoid arthritis |
| topic | arthritis mouse follicular helper T cells glycolysis metabolism |
| url | https://www.frontiersin.org/article/10.3389/fimmu.2018.01973/full |
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