Biotechnology

Pyroptosis

In vivo

Biology

Neuroinflammation

Psychiatry

Caspase 1

Caspase 3

Apoptosis

Gene knockdown

Chemistry

Immunology

Inflammation

Inflammasome

Traumatic brain injury

Programmed cell death

Cell biology

Biochemistry

Medicine

Pharmacology

Caspase

Journal of Neuroinflammation

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.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.During the acute post-injury period (0-48 h) in vivo, motor deficits, anti-inflammatory cytokines (TGF-β and IL-10), pro-inflammatory cytokines (IFN-γ, IL-1β, 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.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.

Ablation of caspase-1 protects against TBI-induced pyroptosis in vitro and in vivo