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Microglial pyroptosis as a therapeutic target after traumatic spinal cord injury: current progress and future
Lei Shi1,2,3, Qiheng Qian2, Jiding Xie3
1College of Physical Education, Yangzhou University, Yangzhou, Jiangsu, China.
Abstract:
Traumatic spinal cord injury (TSCI) is a devastating neurological condition with limited therapeutic options and a high likelihood of permanent disability. Among the multifaceted secondary injury mechanisms triggered by TSCI, pyroptosis-an inflammatory form of programmed cell death-has emerged as a key pathological process. In particular, microglial pyroptosis plays a pivotal role in exacerbating neuroinflammation and disrupting tissue homeostasis, thereby amplifying the secondary injury cascade. This review provides a comprehensive overview of the molecular pathways mediating microglial pyroptosis, including canonical (NLRP3-caspase-1-GSDMD), non-canonical (caspase-11-GSDMD), and atypical (caspase-3/8-GSDME/GSDMC) signaling. We also examine recent therapeutic strategies aimed at suppressing microglial pyroptosis-such as extracellular vesicle-based delivery systems, small-molecule compounds, and gene-targeted approaches-and assess their potential to enhance neurological and motor recovery following SCI. By elucidating both the pathological significance and therapeutic promise of microglial pyroptosis, this review offers novel perspectives on its translational potential as a target for spinal cord injury intervention.
Insights
Traumatic spinal cord injury (TSCI) involves microglial pyroptosis, a cell death process worsening inflammation and injury. Targeting this pathway offers new hope for treating spinal cord injury (SCI) and improving recovery.
Area of Science:
- Neuroscience
- Immunology
- Cell Biology
Background:
- Traumatic spinal cord injury (TSCI) leads to severe disability with few treatments.
- Pyroptosis, an inflammatory cell death, is a critical secondary injury mechanism in TSCI.
- Microglial pyroptosis significantly drives neuroinflammation and tissue damage post-TSCI.
Purpose of the Study:
- To review molecular pathways of microglial pyroptosis in TSCI.
- To explore therapeutic strategies targeting microglial pyroptosis for SCI.
- To assess the potential of these therapies for neurological recovery.
Main Methods:
- Comprehensive literature review of microglial pyroptosis.
- Analysis of canonical, non-canonical, and atypical pyroptosis signaling pathways.
- Evaluation of therapeutic approaches including EVs, small molecules, and gene therapy.
Main Results:
- Detailed description of NLRP3-caspase-1-GSDMD, caspase-11-GSDMD, and caspase-3/8-GSDME/GSDMC pathways in microglia.
- Identification of various therapeutic strategies to inhibit microglial pyroptosis.
- Assessment of the efficacy of these strategies in preclinical models of SCI.
Conclusions:
- Microglial pyroptosis is a key driver of secondary injury after TSCI.
- Targeting microglial pyroptosis presents a promising therapeutic avenue for SCI.
- Further research into these interventions could significantly improve patient outcomes and recovery.
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