Conclusion
These findings demonstrate that inhibition of IL-6 trans-signaling with gp130Fc improves long-term functional outcomes in both male and female mice, albeit in a dose-dependent manner. This study provides novel insights into potential therapeutic strategies targeting IL-6 signaling pathways following stroke.
Methods
Recombinant mouse gp130Fc chimera (sgp130) was administered one hour after middle cerebral artery occlusion (MCAO) followed by twice-weekly administration for 2 weeks in mice (8-15 weeks old). Behavioral assessments were done on days 7 and 28 post-MCAO for chronic studies. Flow cytometry was performed on days 3 (blood) and 7 (spleen and brain) to assess IL-6, mIL-6R, and phosphorylated STAT3 expression.
Results
Improved long-term functional outcomes were observed in male, but not female mice. To investigate the differential response in females, ELISA analyses revealed that plasma IL-6 levels increased in both sexes after MCAO, with a more pronounced induction in females. Additionally, circulating sIL-6R levels were significantly higher in females compared to males (p < 0.05) at 24 h post-MCAO. Administering a higher dose of sgp130 (1 mg/kg) to females improved long-term functional outcomes, suggesting that a higher dose is needed to inhibit IL-6 trans-signaling in females effectively. Mechanistically, sgp130 treatment reduced phosphorylated STAT3 expression in brain F4/80 macrophages and increased the expression of mIL-6R on splenic immune cells at day 7 post-MCAO in both sexes.