Inhibition of Glycolysis Reduces Disease Severity in an Autoimmune Model of Rheumatoid Arthritis.
Inhibition of Glycolysis Reduces Disease Severity in an Autoimmune Model of Rheumatoid Arthritis.
复制标题
DOI：
10.3389/fimmu.2018.01973
复制
发表时间：
2018
影响因子：
7.3
通讯作者：
Morel L
中科院分区：
文献类型：
--
作者：
Abboud G;Choi SC;Kanda N;Zeumer-Spataro L;Roopenian DC;Morel L
K/BxN小鼠是由来自KRN品系的T细胞受体转基因CD 4 + T细胞驱动的自发性关节炎模型，所述T细胞受体转基因CD 4 + T细胞被来自NOD品系的H-2g 7等位基因呈递的葡萄糖-6-磷酸异构酶（GPI）肽激活。它是自身免疫性血清阳性关节炎的模型，因为抗GPI IgG的产生对于关节病理学是必要且充分的。高水平抗GPI IgG的产生需要CD 4+滤泡辅助T（Tfh）细胞的扩增。这种扩张的代谢要求从未被描述过。基于二甲双胍和2-脱氧葡萄糖（2DG）组合在狼疮模型中的治疗作用，使效应CD 4 + T细胞的扩增正常化。我们发现，CD 4 + T细胞和在较小程度上，来自K/BxN小鼠的B细胞比KRN对照组更具有代谢活性。因此，用2DG预防性抑制糖酵解显著减少了关节炎症和适应性和先天性免疫细胞的激活，以及致病性自身抗体的产生。然而，与狼疮易感小鼠相反，添加二甲双胍几乎没有有益作用，表明糖酵解是该模型中免疫激活的主要驱动力。我们提出K/BxN小鼠是另一种模型，其中自身反应性Tfh细胞是高度糖酵解的，并且它们的功能可以通过抑制葡萄糖代谢来限制。
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.
登录
查看更多内容
影响因子：
4.6
作者：
Okano T;Saegusa J;Nishimura K;Takahashi S;Sendo S;Ueda Y;Morinobu A
通讯作者：
Morinobu A
DOI：
10.4049/jimmunol.1402527
发表时间：
2016-01-01
期刊：
Journal of immunology (Baltimore, Md. : 1950)
影响因子：
--
作者：
Kang S;Keener AB;Jones SZ;Benschop RJ;Caro-Maldonado A;Rathmell JC;Clarke SH;Matsushima GK;Whitmire JK;Vilen BJ
通讯作者：
Vilen BJ
DOI：
10.1038/nrrheum.2013.147
发表时间：
2013-11
期刊：
Nature reviews. Rheumatology
影响因子：
--
作者：
通讯作者：
--
影响因子：
5.6
作者：
Kang, Kwi Young;Kim, Young Kyun;Ju, Ji Hyeon
通讯作者：
Ju, Ji Hyeon
影响因子：
7.3
作者：
Christensen AD;Haase C;Cook AD;Hamilton JA
通讯作者：
Hamilton JA