Inhibition of Glycolysis Reduces Disease Severity in an Autoimmune Model of Rheumatoid Arthritis

Abstract

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.

Immune metabolism regulation of the germinal center response

“…These autoimmune-associated phenotypes are reversed by the inhibition of glucose metabolism with 2DG. This glucose-dependence of autoreactive T FH cells was not model-dependent, since it was consistently observed in three other models of spontaneous lupus 8 , induced lupuslike autoimmunity 38 , as well as in the K/BxN autoantibody-dependent model of rheumatoid arthritis 8,39 . On the other hand, the generation of pathogenspecific T FH cells is not impaired by glycolysis inhibition in either lupus-prone or non-autoimmune mice 8 .…”

Immunometabolism: From basic mechanisms to translation

“…A variety of metabolic inhibitors have been tested in animal models of SLE. [80][81][82] Inhibitors of mTORC1 have shown some promise, and direct inhibition of glycolysis may also protect from disease. This effect was strengthened, however, by addition of the AMPK activator, metformin.…”

Immunometabolism in the development of rheumatoid arthritis

“…Triggering of the TCR is coupled to the induction of a metabolic program that enhances mitochondrial function, but also upregulates extramitochondrial glycolysis to generate fast ATP and deliver glucose to the pentose phosphate pathway (PPP) for generation of biosynthetic precursor molecules. Naive CD4 T cells from RA patients fundamentally change the assignment of glucose to the different pathways, minimizing breakdown into pyruvate and lactate and maximizing shunting into the PPP (Figure ). The observation that RA T cells fail to upregulate the key glycolytic enzyme 6‐phosphofructo‐2‐kinase/fructose‐2,6‐bisphosphatase 3 (PFKFB3) was one of the first hints that patient‐derived cells utilize glucose differently .…”