Methylprednisolone modulates the TFR/TFH balance in EAE neuroinflammation through the PI3K/AKT/FoxO1 and PI3K/AKT/mTOR signaling pathways

Background Methylprednisolone (MP) is a potent glucocorticoid, which can effectively inhibit immune system inflammation and brain tissue damage in MS patients. T Follicular helper (Tfh) cells are a subpopulation of activated CD4 + T cells, while T Follicular regulatory (Tfr) cells, a novel subset of Treg cells, possess specialized abilities to suppress the Tfh-GC response and inhibit antibody production. Dysregulation of either Tfh or Tfr cells has been implicated in the pathogenesis of MS. However, the molecular mechanism underlying the anti-inflammatory effects of MP therapy on experimental autoimmune encephalomyelitis (EAE), a representative model for MS, remains unclear. Purpose This study aimed to investigate the effects of MP treatment on EAE and elucidate its possible molecular mechanisms. Method We evaluated the effects of MP on disease progression, CNS inflammatory infiltration and myelination, microglia and astrocyte activation, as well as Tfr/Tfh differentiation and related molecules/inflammatory factors in EAE. Additionally, western blotting was used to assess protein abundance associated with the PI3K/AKT pathway. Results Our findings demonstrated MP treatment ameliorated clinical symptoms, inflammatory cell infiltration, and myelination. Furthermore, it reduced microglia and astrocyte activation. MP up-regulated the differentiation of Tfr cells and cytokine TGF-β1, while downregulating Tfh cells differentiation and cytokine IL-21, as well as regulating the imbalanced Tfr/Tfh ratio in EAE. The PI3K/AKT/FoxO1 and PI3K/AKT/mTOR pathways were found to be involved in EAE development; however, MP treatment inhibited their activation. Conclusion MP demonstrated the ability to reduce neuroinflammation in EAE by regulating the balance between Tfr/Tfh cells via inhibition of the PI3K/ AKT/FoxO1 and PI3K/AKT/mTOR signaling pathway.