Journal
JOURNAL OF NEUROINFLAMMATION
Volume 15, Issue -, Pages -Publisher
BMC
DOI: 10.1186/s12974-018-1083-y
Keywords
TBI; Inflammation; Neuroinflammation; Pyroptosis; Caspase-1; Neuron damage
Categories
Funding
- Shaanxi Fourth People Hospital [2017SY-006]
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Background: Traumatic brain injury (TBI) is a critical public health and socioeconomic problem throughout the world. Inflammation-induced secondary injury is one of the vital pathogenic parameters of TBI. Molecular signaling cascades of pyroptosis, a specific type of cellular necrosis, are key drivers of TBI-induced inflammation. Methods: In this study, mice with genetically ablated caspase-1 (caspase-1(-/-)) were subjected to controlled cortical impact injury in vivo, and primary neuron deficient in caspase-1 through siRNA knockdown and pharmacologic inhibition was stimulated by mechanical scratch, equiaxial stretch, and LPS/ATP in vitro. We evaluated the effects of caspase-1 deficiency on neurological deficits, inflammatory factors, histopathology, cell apoptosis, and pyroptosis. Results: During the acute post-injury period (0-48 h) in vivo, motor deficits, anti-inflammatory cytokines (TGF-beta and IL-10), pro-inflammatory cytokines (IFN-gamma, IL-1 beta, and IL-18), and blood lactate dehydrogenase (LDH), as well as pyroptosis-related proteins (caspase-1, caspase-1 fragments, caspase-11 and GSDMD), were increased. Caspase-1 was activated in the cortex of TBI mice. Inflammatory activation was more profound in injured wild-type mice than in caspase-1(-/-) mice. In vitro, mechanical scratch, equiaxial stretch, and LPS/ATP-induced neuron pyroptosis, apoptosis, LDH release, and increased expression of inflammatory factors. The effects of mechanical and inflammatory stress were reduced through inhibition of caspase-1 activity through siRNA knockdown and pharmacologic inhibition. Conclusion: Collectively, these data demonstrate that pyroptosis is involved in neuroinflammation and neuronal injury after TBI, and ablation of caspase-1 inhibits TBI-induced pyroptosis. Our findings suggest that caspase-1 may be a potential target for TBI therapy.
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