Mesencephalic astrocyte-derived neurotrophic factor attenuates sepsis-associated encephalopathy by inhibiting oxidative stress and pyroptosis.

BACKGROUND

Sepsis-associated encephalopathy (SAE) is a diffuse form of brain dysfunction, and the mechanism of SAE remains unclear. Mesencephalic astrocyte-derived neurotrophic factor (MANF) has been reported to play key roles in inhibiting the inflammatory response, but the specific role of MANF in SAE remains to be fully elucidated.

METHODS

We compared the MANF content between healthy individuals and septic individuals. We established an SAE model in wild-type (WT) and mono-macrophage specific MANF knockout (MKO) mice and detected MANF expression in SAE mice. The rhMANF protein was used to observe the effect and mechanism of MANF on SAE-associated behavioral changes, inflammatory biomarkers and microglial activation, polarization and pyroptosis in SAE mice.

RESULTS

MANF levels were significantly elevated in the serum and circulating monocytes of septic individuals. LPS-induced SAE increased the expression of MANF in the prefrontal cortex, monocytes and macrophages, whereas MKO aggravated peripheral neuropathy and neuroinflammation in SAE mice. rhMANF treatment alleviated SAE-associated delirium-like behavioral changes and reduced the production of proinflammatory cytokines in the prefrontal cortex and serum of SAE mice. Additionally, rhMANF inhibited microglial activation, oxidative stress and Caspase 11-GSDMD-dependent microglial pyroptosis both in vivo and in vitro.

CONCLUSION

The results of the present study indicate that MANF alleviates SAE, likely by inhibiting ROS-GSDMD-dependent microglial pyroptosis.