Abstract
BackgroundTraumatic brain injury remains a significant cause of death and disability in the USA. Currently, there are no effective therapies to mitigate disability except for surgical interventions necessitating a need for continued research into uncovering novel therapeutic targets. In a recent study, we used a rodent model of penetrating traumatic brain injury known as penetrating ballistic-like brain injury (PBBI) to examine the role of innate immunity in post-traumatic secondary injury mechanisms. We previously reported that the inflammasome, a multiprotein complex composed of apoptosis-associated speck-like protein containing card and caspase-1, plays a role in secondary cell death mechanisms after PBBI, including inflammatory cell death (pyroptosis).MethodsIn the current study, we used flow cytometry analysis to evaluate activated microglia and CD11b-positive leukocytes after PBBI and assessed inflammasome activation and pyroptosis of specific cellular populations. Sprague-Dawley male rats underwent PBBI or sham-operated procedures and ipsilateral cortical regions processed for flow cytometry and cellular analysis. Flow cytometry results were compared using one-way ANOVA followed by Tukey’s multiple comparisons.ResultsAt 48 h following PBBI, there was an increase in activated microglia and infiltrating leukocytes compared to sham controls that were associated with increased caspase-1 activity. Using a florescent probe to identify caspase-1 activity and a fluorescent assay to determine cell viability, evidence for pyroptosis in CD11b+ cells was also determined. Finally, while post-traumatic treatment with an anti-ASC antibody had no effect on the number of activated microglia and infiltrating leukocytes, antibody treatment decreased caspase-1 activity in both resident microglia and infiltrating leukocytes and reduced pyroptotic CD11b+ cell death.ConclusionsThese results provide evidence for inflammasome activation in microglia and infiltrating leukocytes after penetrating traumatic brain injury and a role for pyroptotic cell death in the pathophysiology. In addition to inhibiting neuronal cell death, therapeutic treatments targeting inflammasome activation may also provide beneficial effects by reducing the potentially detrimental consequences of activated microglia and infiltrating CD11b+ leukocytes following penetrating traumatic brain injury.
Highlights
Traumatic brain injury remains a significant cause of death and disability in the USA
We used a rodent model of penetrating ballistic-like brain injury (PBBI) [8, 14] that recapitulates cranial gunshot wound pathology and reported that progressive tissue loss following Penetrating traumatic brain injury (PTBI) involves inflammasome activation resulting in initiation of the pyroptosis [16], a form of inflammatory cell death [17,18,19,20,21]
PBBI induces an increase in activated microglia and infiltrating leukocytes, and anti-a caspase recruitment domain (ASC) treatment has no significant effect on numbers of activated microglia or infiltrating leukocytes Flow cytometry analysis of cortical tissue was used to separate populations of resident microglia and infiltrating cells including neutrophils and macrophages as previously described [55]
Summary
Traumatic brain injury remains a significant cause of death and disability in the USA. We previously reported that the inflammasome, a multiprotein complex composed of apoptosis-associated speck-like protein containing card and caspase-1, plays a role in secondary cell death mechanisms after PBBI, including inflammatory cell death (pyroptosis). Several reports have suggested that cells in the injury core undergo a variety of cell death mechanisms, including necrosis and apoptosis [9, 11,12,13,14,15]. We used a rodent model of penetrating ballistic-like brain injury (PBBI) [8, 14] that recapitulates cranial gunshot wound pathology and reported that progressive tissue loss following PTBI involves inflammasome activation resulting in initiation of the pyroptosis [16], a form of inflammatory cell death [17,18,19,20,21]. The precise cell types undergoing pyroptosis after PTBI remain unclear previous studies have provided evidence that this type of cell death can occur in neurons and inflammatory cell populations under a variety of conditions [20, 26,27,28,29]
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