Glycolysis inhibition functionally reprograms T follicular helper cells and reverses lupus
Elshikha, A.; Ge, Y.; Choi, S. C.; Park, Y. P.; Padilla, L.; Zhu, Y.; Clapp, W. L.; Sobel, E. S.; Mohamadzadeh, M.; Morel, L.
Show abstract
Systemic lupus erythematosus (SLE) is an autoimmune disease in which the production of pathogenic autoantibodies depends on T follicular helper (TFH) cells. This study was designed to investigate the mechanisms by which inhibition of glycolysis with 2-deoxy-d-glucose (2DG) reduces the expansion of TFH cells and the associated autoantibody production in lupus-prone mice. Integrated cellular, transcriptomic, epigenetic and metabolic analyses showed that 2DG reversed the enhanced cell expansion and effector functions, as well as mitochondrial and lysosomal defects in lupus TFH cells, which include an increased chaperone-mediated autophagy induced by TLR7 activation. Importantly, adoptive transfer of 2DG-reprogrammed TFH cells protected lupus-prone mice from disease progression. Orthologs of genes responsive to 2DG in murine lupus TFH cells were overexpressed in the TFH cells of SLE patients, suggesting a therapeutic potential of targeting glycolysis to eliminate aberrant TFH cells and curb the production of autoantibodies inducing tissue damage.
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