Traumatic brain injury‐induced neuronal damage in the somatosensory cortex causes formation of rod‐shaped microglia that promote astrogliosis and persistent neuroinflammation

Witcher, Kristina G.; Bray, Chelsea E; Dziabis, Julia E.; McKim, Daniel B.; Benner, Brooke; Rowe, Rachel K.; Kokiko-Cochran, Olga N.; Popovich, Phillip G.; Lifshitz, Jonathan; Eiferman, Daniel; Godbout, Jonathan P.

doi:10.1002/glia.23523

Cited by 124 publications

(142 citation statements)

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“…Although previous data regarding the effects of microglial depletion on acute GFAP changes after TBI are conflicting (Witcher et al, 2018), we did not observe significant changes in GFAP expression or morphology at chronic timepoints after TBI. Reported differences of PLX5622 treatment on posttraumatic astrocyte reactivity may reflect differences in the injury model (midline fluid percussion vs controlled cortical injury), time-points examined (3 days vs 3 months post-injury), or the treatment paradigm employed (pre-treatment vs late posttrauma treatment).…”

Section: Discussioncontrasting

confidence: 97%

“…Reported differences of PLX5622 treatment on posttraumatic astrocyte reactivity may reflect differences in the injury model (midline fluid percussion vs controlled cortical injury), time-points examined (3 days vs 3 months post-injury), or the treatment paradigm employed (pre-treatment vs late posttrauma treatment). In addition, Witcher et al reported that depletion of microglia prior to TBI did not alter injury-induced neuronal injury in the cortex at 7 days post-injury (Witcher et al, 2018). In contrast, our study demonstrates that delayed depletion of microglia during the chronic stages of TBI significantly reduce neuronal cell loss in cortex and hippocampus.…”

Section: Discussioncontrasting

confidence: 73%

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Microglial depletion with CSF1R inhibitor during chronic phase of experimental traumatic brain injury reduces neurodegeneration and neurological deficits

Henry

Ritzel

Barrett

et al. 2019

Preprint

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Chronic neuroinflammation with sustained microglial activation occurs following moderate-to-severe traumatic brain injury (TBI) and is believed to contribute to subsequent neurodegeneration and neurological deficits. Microglia, the primary innate immune cells in brain, are dependent on colony stimulating factor 1 receptor (CSF1R) signaling for their survival. In this translational study, we examined the effects of delayed depletion and subsequent repopulation of microglia on chronic neurodegeneration and functional recovery up to three months posttrauma. A CSF1R inhibitor, PLX5622, was administered to injured adult male C57Bl/6 mice at one month after controlled cortical impact to remove chronically activated microglia, and the inihibitor was withdrawn 1 week later to allow microglial repopulation. Following TBI, the repopulated microglia displayed a ramified morphology, similar to that of sham control uninjured animals, whereas microglia in untreated injured animals showed the typical chronic posttraumatic hypertrophic morphology. PLX5622 treatment limited TBIassociated neuropathological changes at 3 months posttrauma; these included a smaller cortical lesion, reduced neuronal cell death in the injured cortex and ipsilateral hippocampus, and decreased NOX2-dependent reactive microgliosis. Furthermore, delayed depletion of microglia led to widespread changes in the cortical transcriptome, including alterations in gene pathways involved in neuroinflammation, oxidative stress, and neuroplasticity.PLX5622 treated animals showed significantly improved neurological recovery using a variety of complementary neurobehavioral evaluations.These included beam walk and rotorod tests for sensori-motor function, as well as Ymaze, novel object recognition, and Morris water maze tests to evaluate cognitive function. Together, our findings show that chronic phase removal of neurotoxic microglia using CSF1R inhibitors after experimental TBI can markedly reduce chronic neuroinflammation and neurodegeneration, as well as related long-term motor and cognitive deficits. Thus, CSF1R inhibition may provide a clinically feasible approach to limit posttraumatic neurodegeneration and neurological dysfunction following head injury.with neurobehavioral assessment and histology. Rodney M. Ritzel contributed with experimental design, collected and performed data analysis of flow cytometry; James P. Barrett contributed to data collection and PCR analysis; Sarah J. Doran contributed to data collection and IHC analysis; Yun Jiao performed nanostring data analysis; Jennie B. Leach contributed to nanostring data analysis; Gregory L. Szeto contributed to nanostring data analysis and manuscript preparation; Bogdan A. Stoica contributed with experimental design; Alan I. Faden contributed with manuscript preparation; David J. Loane contributed to study conception and design, and manuscript preparation. All authors read and approved the manuscript prior to submission.

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Section: Discussioncontrasting

confidence: 97%

Section: Discussioncontrasting

confidence: 73%

Microglial depletion with CSF1R inhibitor during chronic phase of experimental traumatic brain injury reduces neurodegeneration and neurological deficits

Henry

Ritzel

Barrett

et al. 2019

Preprint

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“…Neuroinflammation and gliosis can often persist for months or even years post-brain trauma [8,10,53,55]. The physiological processes involved in prolonging the inflammatory state of the TBI brain remain poorly defined.…”

Section: Discussionmentioning

confidence: 99%

“…To explore how pre-existing meningeal lymphatic dysfunction influences neuroinflammation in TBI we first investigated changes in GFAP and Iba1 staining, as aggravated gliosis often correlates with worsened clinical outcomes in TBI [49][50][51][52][53]. We found that possessing defects in the meningeal lymphatic system before TBI (TBI+Visudyne+laser) results in greater distance covered by GFAPexpressing astrocytes surrounding the lesion site at 24 hrs post-injury (Figure 3e,f).…”

Section: Meningeal Lymphatic Dysfunction Predisposes the Brain To Examentioning

confidence: 99%

Meningeal lymphatic dysfunction exacerbates traumatic brain injury pathogenesis

Bolte

Hurt

Smirnov

et al. 2019

Preprint

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Traumatic brain injury (TBI) has emerged as a leading cause of death and disability. Despite being a growing medical issue, the biological factors that promote central nervous system (CNS) pathology and neurological dysfunction following TBI remain poorly characterized. Recently, the meningeal lymphatic system was identified as a critical mediator of drainage from the CNS. In comparison to other peripheral organs, our understanding of how defects in lymphatic drainage from the CNS contribute to disease is limited. It is still unknown how TBI impacts meningeal lymphatic function and whether disruptions in this drainage pathway are involved in driving TBI pathogenesis. Here we demonstrate that even mild forms of brain trauma cause severe deficits in meningeal lymphatic drainage that can last out to at least two weeks post-injury. To investigate a mechanism behind impaired lymphatic function in TBI, we examined how increased intracranial pressure (ICP) influences the meningeal lymphatics, as increased ICP commonly occurs in TBI. We demonstrate that increased ICP is capable of provoking meningeal lymphatic dysfunction. Moreover, we show that pre-existing lymphatic dysfunction mediated by targeted photoablation before TBI leads to increased neuroinflammation and cognitive deficits. These findings provide new insights into both the causes and consequences of meningeal lymphatic dysfunction in TBI and suggest that therapeutics targeting the meningeal lymphatic system may offer strategies to treat TBI.

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“…The period of post-TBI is divided into 3 phases: an acute phase, a subacute phase, and a chronic phase. Generally, the acute phase is the first 7 days after TBI, the subacute phase is between 7 days and 3 weeks after TBI, and the chronic phase begins 3 to 5 weeks after TBI [2][3][4][5]. To date, the majority of pre-clinical studies have focused on pharmaceutical interventions in neuroprotection in the acute phase of TBI, such as complement inhibition [6], immunomodulation [7], angiotensin II receptor blockage [8], and cerebral infusion of insulin-like growth factor-1 [9].…”

Section: Introductionmentioning

confidence: 99%

The Contribution of Stem Cell Factor and Granulocyte-Colony Stimulating Factor in Reducing Neurodegeneration and Promoting Neural Network Reorganization after Traumatic Brain Injury

Russell

Qiu

et al. 2019

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Background Traumatic brain injury (TBI) is a major cause of death and disability in young adults worldwide. TBI-induced long-term cognitive deficits represent a growing clinical problem.Stem cell factor (SCF) and granulocyte-colony stimulating factor (G-CSF)play a role in neuroprotection and neuronal plasticity.However, the knowledge concerning reparative efficacy of SCF+G-CSF treatment in post-acute TBI recovery remains incomplete. This study aims to determine the effectsof stem cell factor (SCF) and granulocyte colony-stimulating factor (G-CSF) on post-TBI recovery in young adult mice. The controlled cortical impact model of TBI was used for inducing a severe damage in the motor cortex of the right hemisphere in 8-week-old male C57BL mice. The combination treatment of SCF and G-CSF (SCF+G-CSF) was initiated 3 weeks after induction of TBI. Results Severe TBI led to persistent motor functional deficits (Rota-Rod test) and impaired spatial learning and memory (Morris water maze test). SCF+G-CSF treatment significantly improved the severe TBI-impaired spatial learning and memory at 6 weeks post-treatment.TBI also caused significant increases of Fluoro-Jade C positive degenerating neurons in bilateral frontal cortex, striatum and hippocampus, and significant reductions in MAP2+apical dendrites and overgrowth of SMI312+axons in peri-TBI cavity frontal cortex and in the ipsilateral hippocampal CA1 at 24 weeks post-TBI. SCF+G-CSF treatment significantly reduced TBI-induced neurodegeneration in the contralateral frontal cortex and hippocampal CA1, increased MAP2+apical dendrites in the peri-TBI cavity frontal cortex, and prevented TBI-induced axonal overgrowth in both the peri-TBI cavity frontal cortex and ipsilateral hippocampal CA1. Conclusions These findings reveal a novel pathology of axonal overgrowth after TBI and demonstrate a therapeutic potential of SCF+G-CSF in ameliorating TBI-induced long-term neuronal pathology, neural network malformation, and impairments in spatial learning and memory.

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Traumatic brain injury‐induced neuronal damage in the somatosensory cortex causes formation of rod‐shaped microglia that promote astrogliosis and persistent neuroinflammation

Cited by 124 publications

References 56 publications

Microglial depletion with CSF1R inhibitor during chronic phase of experimental traumatic brain injury reduces neurodegeneration and neurological deficits

Microglial depletion with CSF1R inhibitor during chronic phase of experimental traumatic brain injury reduces neurodegeneration and neurological deficits

Meningeal lymphatic dysfunction exacerbates traumatic brain injury pathogenesis

The Contribution of Stem Cell Factor and Granulocyte-Colony Stimulating Factor in Reducing Neurodegeneration and Promoting Neural Network Reorganization after Traumatic Brain Injury

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