Neuroimmune responses in the developing brain following traumatic brain injury

Nasr, Isam; Chun, Young Soo; Kannan, Sujatha

doi:10.1016/j.expneurol.2019.112957

Cited by 51 publications

(38 citation statements)

References 231 publications

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“…In rats with spontaneous seizures, the average seizure severity was Racine score 3.37 AE 0.18 (range, [3][4], and average seizure duration was 97.88 AE 10.20 seconds (range, 50-140 seconds), confirming the risk for post-traumatic epileptogenesis in the experimental model. It is possible that strain differences, use of younger juvenile rats, which are more susceptible to adverse effects of brain injury, 40 implementation of injury on the day after surgery to minimize neuroprotection due to surgical anesthesia, and inclusion criteria based on apnea duration contributed to greater proportion of rats developing spontaneous seizures compared to earlier studies. [41][42][43] To transition our findings on TLR4 modulation of excitability in ex vivo slices to in vivo, we examined whether systemic TLR4 antagonism could modify dentate excitability 1 week after injury.…”

Section: Systemic Tlr4 Antagonism In Vivo Has Opposing Effects On Earmentioning

confidence: 99%

Toll‐like Receptor 4 Signaling in Neurons Enhances Calcium‐Permeable AMPA Receptor Currents and Drives Post‐Traumatic Epileptogenesis

Korgaonkar

Liu

Sekhar

et al. 2020

Annals of Neurology

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Objective Traumatic brain injury is a major risk factor for acquired epilepsies, and understanding the mechanisms underlying the early pathophysiology could yield viable therapeutic targets. Growing evidence indicates a role for inflammatory signaling in modifying neuronal excitability and promoting epileptogenesis. Here we examined the effect of innate immune receptor Toll‐like receptor 4 (TLR4) on excitability of the hippocampal dentate gyrus and epileptogenesis after brain injury. Methods Slice and in vivo electrophysiology and Western blots were conducted in rats subject to fluid percussion brain injury or sham injury. Results The studies identify that TLR4 signaling in neurons augments dentate granule cell calcium‐permeable α‐amino‐3‐hydroxy‐5‐methyl‐4‐isoxazolepropionic acid (AMPA) receptor (CP‐AMPAR) currents after brain injury. Blocking TLR4 signaling in vivo shortly after brain injury reduced dentate network excitability and seizure susceptibility. When blocking of TLR4 signaling after injury was delayed, however, this treatment failed to reduce postinjury seizure susceptibility. Furthermore, TLR4 signal blocking was less efficacious in limiting seizure susceptibility when AMPAR currents, downstream targets of TLR4 signaling, were transiently enhanced. Paradoxically, blocking TLR4 signaling augmented both network excitability and seizure susceptibility in uninjured controls. Despite the differential effect on seizure susceptibility, TLR4 antagonism suppressed cellular inflammatory responses after injury without impacting sham controls. Interpretation These findings demonstrate that independently of glia, the immune receptor TLR4 directly regulates post‐traumatic neuronal excitability. Moreover, the TLR4‐dependent early increase in dentate excitability is causally associated with epileptogenesis. Identification and selective targeting of the mechanisms underlying the aberrant TLR4‐mediated increase in CP‐AMPAR signaling after injury may prevent epileptogenesis after brain trauma. ANN NEUROL 2020;87:497–515

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Section: Systemic Tlr4 Antagonism In Vivo Has Opposing Effects On Earmentioning

confidence: 99%

Toll‐like Receptor 4 Signaling in Neurons Enhances Calcium‐Permeable AMPA Receptor Currents and Drives Post‐Traumatic Epileptogenesis

Korgaonkar

Liu

Sekhar

et al. 2020

Annals of Neurology

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“…A population-based retrospective cohort study revealed that 18% of patients with central nervous system (CNS) infections developed CMHs within one year after the initial infection, 47 times greater than non-CNS infection controls [34]. Infections complicating cerebrovascular accidents have been extensively investigated [35][36][37][38][39][40][41][42][43][44][45][46][47][48][49][50][51][52][53][54]. However, the role of CMHs complicating infections [55][56][57][58], in particular, acute infections, has been poorly explored [34,[59][60][61].…”

Section: Introductionmentioning

confidence: 99%

Annexin A2 depletion exacerbates the intracerebral microhemorrhage induced by acute rickettsia and Ebola virus infections

Chang

Drelich

et al. 2020

PLoS Negl Trop Dis

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Intracerebral microhemorrhages (CMHs) are small foci of hemorrhages in the cerebrum. Acute infections induced by some intracellular pathogens, including rickettsia, can result in CMHs. Annexin a2 (ANXA2) has been documented to play a functional role during intracellular bacterial adhesion. Here we report that ANXA2-knockout (KO) mice are more susceptible to CMHs in response to rickettsia and Ebola virus infections, suggesting an essential role of ANXA2 in protecting vascular integrity during these intracellular pathogen infections. Proteomic analysis via mass spectrometry of whole brain lysates and brain-derived endosomes from ANXA2-KO and wild-type (WT) mice post-infection with R. australis revealed that a variety of significant proteins were differentially expressed, and the follow-up function enrichment analysis had identified several relevant cell-cell junction functions. Immunohistology study confirmed that both infected WT and infected ANXA2-KO mice were subjected to adherens junctional protein (VE-cadherin) damages. However, key blood-brain barrier (BBB) components, tight junctional proteins ZO-1 and occludin, were disorganized in the brains from R. australis-infected ANXA2-KO mice, but not those of infected WT mice. Similar ANXA2-KO dependent CMHs and fragments of ZO-1 and occludin were also observed in Ebola virus-infected ANXA2-KO mice, but not found in infected WT mice. Overall, our study revealed a novel role of ANXA2 in the formation of CMHs during R. australis and Ebola virus infections; and the underlying mechanism is relevant to the role of ANXA2-regulated tight junctions and its role in stabilizing the BBB in these deadly infections.

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“…Increasingly, a number of neurodevelopmental processes have been found to have sex-based differences, yet the impact of these differences on secondary injury after TBI remains understudied. 18,28 In our study, we investigated two different aspects of the neuroinflammatory response to juvenile FPI and found sex-based differences in both. The neuroinflammatory environment after pediatric TBI is of particular interest, given that during development, microglia exist in a more activated stated attributable to their role in synaptic pruning and phagocytosis.…”

Section: Discussionmentioning

confidence: 93%

A Mouse Model for Juvenile, Lateral Fluid Percussion Brain Injury Reveals Sex-Dependent Differences in Neuroinflammation and Functional Recovery

Newell

Todd

Luo

et al. 2020

Journal of Neurotrauma

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Traumatic brain injury (TBI) is a leading cause of death and disability that lacks targeted therapies. Successful translation of promising neuroprotective therapies will likely require more precise identification of target populations through greater study of crucial biological factors like age and sex. A growing body of work supports the impact of these factors on response to and recovery from TBI. However, age and sex are understudied in TBI animal models. The first aim of this study was to demonstrate the feasibility of lateral fluid percussion injury (FPI) in juvenile mice as a model of pediatric TBI. Subsequently, we were interested in examining the impact of young age and sex on TBI outcome. After adapting the lateral FPI model to 21-day-old male and female mice, we characterized the molecular, histological, and functional outcomes. Whereas similar tissue injury was observed in male and female juvenile mice exposed to TBI, we observed differences in neuroinflammation and neurobehavioral function. Overall, our findings revealed less acute inflammatory cytokine expression, greater subacute microglial/macrophage accumulation, and greater neurological recovery in juvenile male mice after TBI. Given that ongoing brain development may affect progression of and recovery from TBI, juvenile models are of critical importance. The sex-dependent differences we discovered after FPI support the necessity of also including this biological variable in future TBI studies. Understanding the mechanisms underlying age-and sex-dependent differences may result in the discovery of novel therapeutic targets for TBI.

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Neuroimmune responses in the developing brain following traumatic brain injury

Cited by 51 publications

References 231 publications

Toll‐like Receptor 4 Signaling in Neurons Enhances Calcium‐Permeable AMPA Receptor Currents and Drives Post‐Traumatic Epileptogenesis

Toll‐like Receptor 4 Signaling in Neurons Enhances Calcium‐Permeable AMPA Receptor Currents and Drives Post‐Traumatic Epileptogenesis

Annexin A2 depletion exacerbates the intracerebral microhemorrhage induced by acute rickettsia and Ebola virus infections

A Mouse Model for Juvenile, Lateral Fluid Percussion Brain Injury Reveals Sex-Dependent Differences in Neuroinflammation and Functional Recovery

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