Shengxian decoction alleviates experimental autoimmune myasthenia gravis by enhancing the immunosuppressive activity of regulatory T cells via Hippo pathway.

ETHNOPHARMACOLOGICAL RELEVANCE

Myasthenia gravis (MG) is an autoimmune disease mediated by autoantibodies, the pathogenesis of which is well defined but for which safe and effective drugs are still lacking. Shengxian Decoction (SXD) is a classical Chinese herbal formula that has been shown to improve qi deficiency and fatigue syndrome, which is also one of the key pathomechanisms in myasthenia gravis. However, the potential of this formula to treat myasthenia gravis (MG) and its underlying mechanisms remains to be fully elucidated.

AIM OF THE STUDY

To investigate the therapeutic effect of the traditional Chinese medicine formula, Shengxian Decoction (SXD) on MG and its potential mechanism of action.

METHODS AND MATERIALS

Employing prednisone (PDN) as a positive control, the experimental autoimmune myasthenia gravis (EAMG) rat model induced by recombinant acetylcholine receptor (AChR) α subunit 97-116 peptide was used to reveal and confirm the therapeutic effect of SXD on MG. Model evaluation was performed based on animal behavioral performance combined with repeated nerve stimulation (RNS) experiments. Hematoxylin-Eosin (HE) staining and enzyme-linked immunosorbent (ELISA) assay were used to detect the level of inflammatory cytokines. The alterations in T-cell immunity were observed using flow cytometry (FCM). Immunohistochemistry (IHC) and immunofluorescence (IF) experiments were used to detect the molecular expression of TAZ, TEAD, and FOXP3. The ex vivo and in vivo mechanisms were validated by Western blot (WB) and Co-immunoprecipitation (Co-IP).

RESULTS

The results showed that SXD significantly reversed loss of weight and muscle strength in EAMG rats, reducing the inflammation level and repairing the damage of thymic tissues in the model rats. Furthermore, SXD altered the trend observed in EAMG rats by markedly increasing the proportion of pro-inflammatory Th1 and Th17 cells and reducing the expression of Regulatory T cells (Treg), which plays a pivotal role in regulating the immune response in EAMG rats. SXD was shown to upregulate the expression of FOXP3 and TEAD, downregulate the expression of TAZ, and inhibit the binding of TAZ and TEAD in this research. This phenomenon was subsequently validated in vitro, which may elucidate the potential mechanism of SXD in the treatment of EAMG.

CONCLUSION

SXD has been demonstrated to possess the capacity to treat EAMG. The underlying mechanism of action may be achieved by promoting the degradation of TAZ through the TAZ/TEAD pathway and inhibiting the binding of TAZ and TEAD, thereby restoring the balance of the body's immune function.