Interfering with the Chronic Immune Response Rescues Chronic Degeneration After Traumatic Brain Injury

Ertürk, Ali; Mentz, Susanne; Stout, Erik E; Hedehus, Maj; Domínguez, Sara L.; Neumaier, Lisa; Krammer, Franziska; Llovera, Gemma; Srinivasan, Karpagam; Hansen, David V.; Liesz, Arthur; Scearce‐Levie, Kimberly; Sheng, Morgan

doi:10.1523/jneurosci.1898-15.2016

Cited by 81 publications

(77 citation statements)

References 78 publications

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“…Because vDISCO fluorescent signal boosting allows both imaging and quantifications on light-sheet microscopy images of transparent mouse bodies, we identified TBI-induced changes at the peripheral axonal projections innervating the skeletal musculature of the torso. These data are in line with our recent results demonstrating functional deficits in fine motor movements in mice upon TBI in the same experimental model 40 . Here, we also demonstrated that meningeal vessels extending between the cranium and CNS tissue and their cellular content can readily be imaged by vDISCO panoptic imaging in naïve animals and acute CNS injury models (stroke and spinal cord injury).…”

Section: Discussionsupporting

confidence: 93%

Panoptic vDISCO imaging reveals neuronal connectivity, remote trauma effects and meningeal vessels in intact transparent mice

Cai

Pan

Ghasemigharagoz

et al. 2018

Preprint

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Note: Manuscript videos are available at 'Supplementary material' section of BioRxiv and at the following link http://vdisco.isd-muc.de/ Abstract Analysis of entire transparent rodent bodies could provide holistic information on biological systems in health and disease. However, it has been challenging to reliably image and quantify signal from endogenously expressed fluorescent proteins in large cleared mouse bodies due to the low signal contrast. Here, we devised a pressure driven, nanobody based whole-body immunolabeling technology to enhance the signal of fluorescent proteins by up to two orders of magnitude. This allowed us to image subcellular details in transparent mouse bodies through bones and highly autofluorescent tissues, and perform quantifications. We visualized for the first-time whole-body neuronal connectivity of an entire adult mouse and discovered that brain trauma induces degeneration of peripheral axons. We also imaged meningeal lymphatic vessels and immune cells through the intact skull and vertebra in naïve animals and trauma models. Thus, our new approach can provide an unbiased holistic view of biological events affecting the nervous system and the rest of the body.

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Section: Discussionsupporting

confidence: 93%

Panoptic vDISCO imaging reveals neuronal connectivity, remote trauma effects and meningeal vessels in intact transparent mice

Cai

Pan

Ghasemigharagoz

et al. 2018

Preprint

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“…As stated before, the Il6 ΔMic mice are also haploinsufficient for Cx3Cr1 , which might have an effect on its own independent of the microglial IL‐6 deficiency (Dénes, Ferenczi, Halász, Környei, & Kovács, ; Ertürk et al, ; Rogers et al, ). However, it is rather unlikely that heterozygous mice for this gene, in contrast to Cx3Cr1 KO, would have a major phenotype per se.…”

Section: Resultsmentioning

confidence: 90%

“…For instance, while the total absence of CX3CR1 affected cognitive functions of the mice in basal conditions, it did not influence spontaneous locomotor activity or anxiety levels (Rogers et al, 2011). Regarding TBI, no significant differences in the rotarod between lesioned-WT and lesioned-Cx3Cr1 Hz males and females were observed during the first 18 dpi by Ertürk et al (2016). Furthermore, in another study the volume of the lesion was reduced in lesioned-Cx3Cr1 KO compared to lesioned-Cx3Cr1 Hz and WT mice, but no differences between the latter two groups were observed at 24 and 72 hr after the lesion (Dénes et al, 2008).…”

Section: Effect Of Microglial Il6 Deficiency On the Responses To Crmentioning

confidence: 91%

Microglial cell‐derived interleukin‐6 influences behavior and inflammatory response in the brain following traumatic brain injury

Sanchís

Fernández-Gayol

Vizueta

et al. 2019

Glia

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Traumatic brain injury (TBI) is a major health problem with high rates of mortality and morbidity worldwide. The response of the brain to TBI is orchestrated by a number of cytokines, including interleukin‐6 (IL‐6). IL‐6 is a major cytokine in the central nervous system and it is produced by different cells, such as neurons, glial cells, and endothelial cells. Since glial cells are one of the most important sources and targets of IL‐6, we have examined the role of microglia‐derived IL‐6 in normal conditions and following a model of TBI, cryolesion of the somatosensorial cortex. To this end, tamoxifen‐inducible microglial IL‐6‐deficient (Il6ΔMic, using Cx3cr1 CreER model) mice and control (Il6lox/lox) mice were used. In normal conditions, microglial IL‐6 deficiency reduced deambulation and exploratory behavior and decreased anxiety in a sex‐dependent manner. The transcriptome profile following cryolesion was dramatically altered 1 day post‐lesion in Il6ΔMic compared with Il6lox/lox mice. However, the phenotype of Il6ΔMic mice was less compromised in the following days, suggesting that compensatory mechanisms are at play.

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“…2, at 37 dpi), but rather that ISRIB has produced enduring changes to memory processes during the treatment period, such as dendritic spine remodeling. Previous work has established that TBI acutely induces significant dendritic spine degeneration (63), and dendritic spine loss persists even a year after a severe TBI (64). In addition, pharmacological induction of eIF2α phosphorylation in chicks blocks training-induced increase in the number of spines in an auditory brain area (24).…”

Section: Discussionmentioning

confidence: 99%

Inhibition of the integrated stress response reverses cognitive deficits after traumatic brain injury

Chou

Krukowski

Jopson

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

197

213

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Traumatic brain injury (TBI) is a leading cause of long-term neurological disability, yet the mechanisms underlying the chronic cognitive deficits associated with TBI remain unknown. Consequently, there are no effective treatments for patients suffering from the long-lasting symptoms of TBI. Here, we show that TBI persistently activates the integrated stress response (ISR), a universal intracellular signaling pathway that responds to a variety of cellular conditions and regulates protein translation via phosphorylation of the translation initiation factor eIF2α. Treatment with ISRIB, a potent drug-like small-molecule inhibitor of the ISR, reversed the hippocampaldependent cognitive deficits induced by TBI in two different injury mouse models-focal contusion and diffuse concussive injury. Surprisingly, ISRIB corrected TBI-induced memory deficits when administered weeks after the initial injury and maintained cognitive improvement after treatment was terminated. At the physiological level, TBI suppressed long-term potentiation in the hippocampus, which was fully restored with ISRIB treatment. Our results indicate that ISR inhibition at time points late after injury can reverse memory deficits associated with TBI. As such, pharmacological inhibition of the ISR emerges as a promising avenue to combat head traumainduced chronic cognitive deficits.brain trauma | memory deficits | translational control | eIF2α | hippocampus T raumatic brain injury (TBI) represents a major mental health problem (1-4). Even a mild TBI can elicit cognitive deficits, including permanent memory dysfunction (2, 4). Moreover, TBI is one of the most predictive environmental risk factors for the development of Alzheimer's disease and other forms of dementia (5-9). Current treatments have focused primarily on reducing the risk of TBI incidence, immediate neurosurgical intervention, or broad behavioral rehabilitation (10-13). Despite posing a huge societal problem, there are currently no pharmacological treatment options for patients that suffer from TBIinduced cognitive deficits.The integrated stress response (ISR) is an evolutionarily conserved pathway that controls cellular homeostasis and function (14). The central ISR regulatory step is the phosphorylation of the α-subunit of the eukaryotic translation initiation factor 2 (eIF2α) by a family of four eIF2α kinases (15, 16). Phosphorylation of eIF2α leads to inhibition of general protein synthesis, but also, to the translational up-regulation of a select subset of mRNAs (17, 18). In the brain, phosphorylation of eIF2α regulates the formation of long-term memory (19)(20)(21). Briefly, animals with reduced phosphorylation of eIF2α show enhanced long-term memory storage (19,(22)(23)(24), and increased phosphorylation of eIF2α in the brain prevents the formation of long-term memory (19,24,25).Similar to other chronic cognitive disorders (21, 26), TBI leads to a persistent activation of the ISR. TBI induces eIF2α phosphorylation even in brain regions that are distal to the injury site (27, 28). How...

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Interfering with the Chronic Immune Response Rescues Chronic Degeneration After Traumatic Brain Injury

Cited by 81 publications

References 78 publications

Panoptic vDISCO imaging reveals neuronal connectivity, remote trauma effects and meningeal vessels in intact transparent mice

Panoptic vDISCO imaging reveals neuronal connectivity, remote trauma effects and meningeal vessels in intact transparent mice

Microglial cell‐derived interleukin‐6 influences behavior and inflammatory response in the brain following traumatic brain injury

Inhibition of the integrated stress response reverses cognitive deficits after traumatic brain injury

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