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Published on: January 30, 2014
Sirtuin 1 alleviates microglia-induced inflammation by modulating the PGC-1α/Nrf2 pathway after traumatic brain
Xiangrong Chen1, Guan Wei2, Ding Li3
1Department of Neurosurgery, The Second Affiliated Hospital, Fujian Medical University, Quanzhou 362000, Fujian Province, China.
Abstract:
Microglial activation and the subsequent inflammatory response play important roles in the central nervous system after traumatic brain injury (TBI). Activation of the PGC-1α pathway is responsible for microglial activation after TBI. Our previous study demonstrated that SIRT1 alleviates neuroinflammation-induced apoptosis after TBI, and activation of the PGC-1α/Nrf2 pathway extenuates TBI-induced neuronal apoptosis. However, no study has investigated whether SIRT1 can affect the PGC-1α/Nrf2 pathway to induce microglial excitation and the subsequent neuroinflammatory response. Microglial activation and the levels of pro-inflammatory factors, namely, tumor necrosis factor (TNF-α), interleukin-1β (IL-1β), and interleukin-6 (IL-6) were assessed to evaluate the neuroinflammatory response after TBI. To examine the effects of SIRT1, immunohistochemical staining and western blot analysis were used to observe the nuclear translocation and secretion of PGC-1α, as well as the activation of the PGC-1α/Nrf2 pathway. Treatment with the SIRT1 inhibitor sirtinol promoted microglial activation and pro-inflammatory factor expression (TNF-α, IL-6, and IL-1β) and inhibited PGC-1α and Nrf2 nuclear translocation and secretion after TBI, while treatment with the SIRT1 activator A3 had the opposite effects. The results of this study suggest that microglial activation, the subsequent neuroinflammatory response, and the PGC-1α/Nrf2 pathway play essential roles in secondary injury after TBI. These results indicate that SIRT1 protects neurons after TBI by inhibiting microglial activation and the subsequent inflammatory response, possibly by activating the PGC-1α/Nrf2 pathway.
Insights
Sirtuin 1 (SIRT1) activation mitigates neuroinflammation after traumatic brain injury (TBI) by inhibiting microglial activation and the PGC-1α/Nrf2 pathway, thereby protecting neurons.
Area of Science:
- Neuroscience
- Cellular Biology
- Pathology
Background:
- Microglial activation and neuroinflammation are critical in central nervous system injury following traumatic brain injury (TBI).
- The PGC-1α pathway mediates microglial activation post-TBI.
- SIRT1 has been shown to reduce TBI-induced neuroinflammation and apoptosis, while the PGC-1α/Nrf2 pathway attenuates neuronal apoptosis.
Purpose of the Study:
- To investigate the role of SIRT1 in regulating microglial activation and the neuroinflammatory response via the PGC-1α/Nrf2 pathway after TBI.
- To determine if SIRT1 influences the PGC-1α/Nrf2 pathway's role in TBI-induced microglial excitation and neuroinflammation.
Main Methods:
- Assessed microglial activation and pro-inflammatory factors (TNF-α, IL-1β, IL-6) to evaluate neuroinflammation post-TBI.
- Utilized immunohistochemical staining and western blot analysis to examine PGC-1α nuclear translocation and secretion, and PGC-1α/Nrf2 pathway activation.
- Administered SIRT1 inhibitor (sirtinol) and activator (A3) to observe their effects on TBI models.
Main Results:
- Inhibition of SIRT1 (sirtinol) exacerbated microglial activation and pro-inflammatory cytokine expression while suppressing PGC-1α and Nrf2 nuclear translocation.
- Activation of SIRT1 (A3) demonstrated opposing effects, reducing microglial activation and inflammation and promoting PGC-1α/Nrf2 pathway activation.
- These findings link SIRT1 activity to the modulation of the PGC-1α/Nrf2 pathway in the context of TBI.
Conclusions:
- Microglial activation, neuroinflammation, and the PGC-1α/Nrf2 pathway are key contributors to secondary injury following TBI.
- SIRT1 plays a protective role in TBI by inhibiting microglial activation and neuroinflammation, potentially through the activation of the PGC-1α/Nrf2 pathway.
- Targeting SIRT1 may represent a therapeutic strategy for managing TBI-related neuroinflammation and neuronal damage.
