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A Ferret Model of Inflammation-sensitized Late Preterm Hypoxic-ischemic Brain Injury
Published on: November 19, 2019
Fetuin-A alleviates neuroinflammation against traumatic brain injury-induced microglial necroptosis by regulating
Pengzhan Zhao1,2, Yutian Wei1, Guangchi Sun1
1Department of Neurosurgery, The First Affiliated Hospital of Nanjing Medical University, Nanjing, 210029, Jiangsu, China.
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.
Insights
Fetuin-A reduces brain damage after traumatic brain injury (TBI) by suppressing microglial necroptosis and inflammation. This liver glycoprotein activates the Nrf-2/HO-1 pathway, mitigating oxidative stress and offering a potential TBI therapy.
Area of Science:
- Neuroscience
- Immunology
- Biochemistry
Background:
- Microglia-mediated inflammation is key in secondary damage after traumatic brain injury (TBI).
- The precise mechanisms driving microglial activation in TBI remain unclear.
- Understanding microglial activation is crucial for developing effective TBI treatments.
Purpose of the Study:
- To investigate the role of Fetuin-A in TBI.
- To elucidate the mechanisms by which Fetuin-A influences microglial activation and inflammatory responses.
- To explore Fetuin-A as a potential therapeutic agent for TBI.
Main Methods:
- Controlled Cortical Impact (CCI) model in mice and in vitro primary microglia models.
- Quantitative proteomics to identify differentially expressed proteins.
- Western blot, immunostaining, ELISA, and MitoSox Red staining to assess microglial activation, inflammation, and oxidative stress.
- Transmission electron microscopy to observe necroptosis morphology.
- In vivo and in vitro experiments with Fetuin-A administration and Nrf-2/HO-1 pathway modulation.
Main Results:
- Fetuin-A levels increased post-TBI, peaking at 6 hours.
- Fetuin-A administration reduced lesion volume, edema, and inflammation by suppressing microglial necroptosis.
- Fetuin-A attenuated mitochondrial oxidative stress and promoted Nrf-2 nuclear translocation, activating the Nrf-2/HO-1 pathway.
- Inhibition of Nrf-2 or HO-1 reversed Fetuin-A's protective effects, increasing oxidative stress and necroptosis.
Conclusions:
- Fetuin-A activates the Nrf-2/HO-1 pathway, suppressing oxidative stress and necroptosis.
- Fetuin-A effectively attenuates the inflammatory response following TBI.
- Fetuin-A presents a promising therapeutic strategy for TBI treatment.
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