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.