JAK2 inhibitor ameliorates the progression of experimental autoimmune myasthenia gravis and balances Th17/Treg cells via regulating the JAK2/STAT3-AKT/mTOR signaling pathway.

Abstract

An imbalance in Th17/regulatory T (Treg) cells is the major pathogenic mechanism underlying myasthenia gravis (MG). JAK2 inhibitors selectively inhibit JAK2 and reduce inflammatory responses. However, there have been no studies examining the therapeutic effects of JAK2 inhibitors in the context of MG. Here, an experimental autoimmune MG (EAMG) rat model was established to explore the therapeutic effect of JAK2 inhibitors on EAMG rats immunized with the AChR α-subunit (97-116 peptide). A JAK2 inhibitor was administered to EAMG rats both in vivo and in vitro. The following experimental methods were used to evaluate the effects of JAK2 inhibitors. The behavioral scores and body weights of the rats were assessed on alternate days. Serum anti-AChR (97-116) IgG and cytokine levels were detected using ELISA. CD4+ T cell subsets and related transcription factors in mononuclear cells were detected using flow cytometry and qPCR, respectively. The expression levels of protein molecules in the signaling pathway were detected by western blotting, and the neuromuscular junctions were observed using immunofluorescence. The results revealed that JAK2 inhibitors could regulate Th17/Treg balance in vivo and in vitro. JAK2 inhibitors reduced the immune response in EAMG rats (including reducing pro-inflammatory cytokines and postsynaptic membrane complement deposition), improved clinical symptoms, and increased AChR aggregation in the postsynaptic membrane. Meanwhile, this study demonstrated that JAK2 inhibitor treatment suppressed the phosphorylation of JAK2/STAT3 and AKT/mTOR pathways and decreased the expression level of the IL-23 receptor. This study reveals that there is crosstalk between the JAK2/STAT3 and AKT/mTOR pathways in EAMG rats. JAK2 inhibitors can ameliorate EAMG by regulating Th17/Treg balance by inhibiting both signaling pathways. Our study provides new potential therapeutic targets for MG immunotherapy.