The role of microglial inflammasome activation in pyroptotic cell death following penetrating traumatic brain injury
Abstract Background Traumatic 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...
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doaj-284f3ca0a2fa443c94a09de1e1c37f372020-11-25T02:43:57ZengBMCJournal of Neuroinflammation1742-20942019-02-0116111210.1186/s12974-019-1423-6The role of microglial inflammasome activation in pyroptotic cell death following penetrating traumatic brain injuryStephanie W. Lee0Juan Pablo de Rivero Vaccari1Jessie S. Truettner2W. Dalton Dietrich3Robert W. Keane4Department of Neurological Surgery, The Miami Project to Cure Paralysis, University of Miami Miller School of MedicineDepartment of Neurological Surgery, The Miami Project to Cure Paralysis, University of Miami Miller School of MedicineDepartment of Neurological Surgery, The Miami Project to Cure Paralysis, University of Miami Miller School of MedicineDepartment of Neurological Surgery, The Miami Project to Cure Paralysis, University of Miami Miller School of MedicineDepartment of Physiology and Biophysics, University of Miami Miller School of MedicineAbstract Background Traumatic 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). Methods In 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. Results At 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. Conclusions These 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.http://link.springer.com/article/10.1186/s12974-019-1423-6InflammasomeASCPyroptosisMicrogliaInfiltrating leukocytesTraumatic brain injury |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Stephanie W. Lee Juan Pablo de Rivero Vaccari Jessie S. Truettner W. Dalton Dietrich Robert W. Keane |
spellingShingle |
Stephanie W. Lee Juan Pablo de Rivero Vaccari Jessie S. Truettner W. Dalton Dietrich Robert W. Keane The role of microglial inflammasome activation in pyroptotic cell death following penetrating traumatic brain injury Journal of Neuroinflammation Inflammasome ASC Pyroptosis Microglia Infiltrating leukocytes Traumatic brain injury |
author_facet |
Stephanie W. Lee Juan Pablo de Rivero Vaccari Jessie S. Truettner W. Dalton Dietrich Robert W. Keane |
author_sort |
Stephanie W. Lee |
title |
The role of microglial inflammasome activation in pyroptotic cell death following penetrating traumatic brain injury |
title_short |
The role of microglial inflammasome activation in pyroptotic cell death following penetrating traumatic brain injury |
title_full |
The role of microglial inflammasome activation in pyroptotic cell death following penetrating traumatic brain injury |
title_fullStr |
The role of microglial inflammasome activation in pyroptotic cell death following penetrating traumatic brain injury |
title_full_unstemmed |
The role of microglial inflammasome activation in pyroptotic cell death following penetrating traumatic brain injury |
title_sort |
role of microglial inflammasome activation in pyroptotic cell death following penetrating traumatic brain injury |
publisher |
BMC |
series |
Journal of Neuroinflammation |
issn |
1742-2094 |
publishDate |
2019-02-01 |
description |
Abstract Background Traumatic 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). Methods In 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. Results At 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. Conclusions These 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. |
topic |
Inflammasome ASC Pyroptosis Microglia Infiltrating leukocytes Traumatic brain injury |
url |
http://link.springer.com/article/10.1186/s12974-019-1423-6 |
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