Fetuin-A alleviates neuroinflammation against traumatic brain injury-induced microglial necroptosis by regulating Nrf-2/HO-1 pathway

Abstract

Background The microglia-mediated inflammatory response is a vital mechanism of secondary damage following traumatic brain injury (TBI), but the underlying mechanism of microglial activation is unclear. Methods Controlled cortical impact (CCI) was induced in adult male C57BL/6J mice, and glutamate was used to construct a classical in vitro injury model in the primary microglia. Microglial activation was determined by western blot and immunostaining. The inflammatory factors were measured by enzyme-linked immunosorbent assay. The oxidative stress marker and mitochondrial reactive oxygen species (ROS) were measured by immunoblotting and MitoSox Red staining. Transmission electron microscopy was used to observe the typical morphology of necroptotic cells. Results Our quantitative proteomics identified 2499 proteins; 157 were significantly differentially expressed in brain tissue between the 6 h after CCI (CCI6h) group and sham group, and 109 were significantly differentially expressed between the CCI24h and sham groups. Moreover, compared with the sham group, the terms “acute-phase response”, “inflammation”, and “protein binding” were significantly enriched in CCI groups. Fetuin-A, a liver-secreted acute-phase glycoprotein, was involved in these biological processes. Using an experimental TBI model, we found that the Fetuin-A level peaked at 6 h and then decreased gradually. Importantly, we showed that administration of Fetuin-A reduced the cortical lesion volume and edema area and inhibited the inflammatory response, which was associated with suppressing microglial necroptosis, thus decreasing microglial activation. Furthermore, administration of Fetuin-A attenuated mitochondrial oxidative stress in glutamate-treated microglial cells, which is a critical mechanism of necroptosis suppression. In addition, we demonstrated that Fetuin-A treatment promoted translocation of nuclear factor erythroid 2-related factor 2 (Nrf-2) from the cytoplasm to the nucleus in vivo; however, the Nrf-2 inhibitor ML385 and si-heme oxygenase-1 (si-HO-1) disrupted the regulation of oxidative stress by Fetuin-A and induced increased ROS levels and necroptosis in glutamate-treated microglial cells. Fetuin-A also protected neurons from adverse factors in vivo and in vitro. Conclusions Our results demonstrated that Fetuin-A activated Nrf-2/HO-1, suppressed oxidative stress and necroptosis levels, and thereby attenuates the abnormal inflammatory response following TBI. The findings suggest a potential therapeutic strategy for TBI treatment.

Exogenous fetuin‐A protects against sepsis‐induced myocardial injury by inhibiting oxidative stress and inflammation in mice

“…36 Moreover, the protective effects of fetuin A have also been attributed to a significant decrease in oxidative stress and restoration of anti-oxidative actions. 61 Based on the previous studies and the results of the present study, it may be proposed that the beneficial effects of fetuin A in sepsis-induced myocardial injury may be secondary to a decrease in inflammatory reactions and reduction in oxidative stress. Since fetuin A employed in the present study was derived from the fetal bovine serum (Sigma Aldrich, USA), therefore, fetuin A was not identical to the endogenous fetuin A of Swiss mice.…”

“…Furthermore, it has also been reported that fetuin‐A supplementation significantly inhibits the IFN‐ℽ and endotoxin‐induced HMGB1 (late mediator) release in a concentration‐dependent manner by stimulating macrophages‐mediated phagocytic elimination of apoptotic cells 36 . Moreover, the protective effects of fetuin A have also been attributed to a significant decrease in oxidative stress and restoration of anti‐oxidative actions 61 . Based on the previous studies and the results of the present study, it may be proposed that the beneficial effects of fetuin A in sepsis‐induced myocardial injury may be secondary to a decrease in inflammatory reactions and reduction in oxidative stress.…”

Smart Nanoscale Extracellular Vesicles in the Brain: Unveiling their Biology, Diagnostic Potential, and Therapeutic Applications

“…Another aspect of TBI pathogenesis is increased neuroinflammation postinjury . It has been shown that the microglia undergo necroptosis in TBI, resulting in expanded patient inflammatory profiles. − Though a direct correlation between EVs and the neuroinflammatory cascade in TBI is underexplored, a correlation is suggestive, given the immunomodulatory roles of EVs. Indeed plasma-derived EVs from warfighters display increased levels of cytokines like IL-10, which positively correlated to poor sleep quality in TBI patients .…”

CASK Mediates Oxidative Stress-Induced Microglial Apoptosis-Inducing Factor-Independent Parthanatos Cell Death via Promoting PARP-1 Hyperactivation and Mitochondrial Dysfunction

“…In this study, we first observed that CASK silencing in human CHME3 microglia significantly attenuates H 2 O 2 -induced cell death. Depending on the stress stimuli and cellular contexts, oxidative stress may lead to microglial apoptosis [ 44 ], parthanatos [ 45 ], or necroptosis [ 46 , 47 ]. Our study shows that H 2 O 2 -induced cell death is abrogated by the PARP-1 inhibitor olaparib, suggesting that the CHME3 cells undergo parthanatos under H 2 O 2 treatment.…”