IL-1  Gene Deletion Protects Oligodendrocytes after Spinal Cord Injury through Upregulation of the Survival Factor Tox3

Bastien, Dominic; Landete, V. Bellver; Lessard, Martine; Vallières, Nicolas; Champagne, Marie-Eve; Takashima, Akira; Tremblay, Marie‐Ève; Doyon, Yannick; Lacroix, Steve

doi:10.1523/jneurosci.0498-15.2015

Cited by 59 publications

(56 citation statements)

References 63 publications

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“…Our results concur with other studies using the same setting of 50‐kdyn force impact and mouse impactor tips that indicate a moderate injury of contusion injury (Bastien et al. ). After 3 and 10 days in culture, the high numbers of live cells in the slices indicated the cells survived after the impact, although dead cells were also observed (Fig.…”

Section: Discussionsupporting

confidence: 92%

Cell viability in three ex vivo rat models of spinal cord injury

et al. 2018

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Spinal cord injury (SCI) is a devastating disorder that has a poor prognosis of recovery. Animal models of SCI are useful to understand the pathophysiology of SCI and the potential use of therapeutic strategies for human SCI. Ex vivo models of central nervous system (CNS) trauma, particularly mechanical trauma, have become important tools to complement in vivo models of injury in order to reproduce the sequelae of human CNS injury. Ex vivo organotypic slice cultures (OSCs) provide a reliable model platform for the study of cell dynamics and therapeutic intervention following SCI. In addition, these ex vivo models support the 3R concept of animal use in SCI research – replacement, reduction and refinement. Ex vivo models cannot be used to monitor functional recovery, nor do they have the intact blood supply of the in vivo model systems. However, the ex vivo models appear to reproduce many of the post traumatic events including acute and secondary injury mechanisms. Several well‐established OSC models have been developed over the past few years for experimental spinal injuries ex vivo in order to understand the biological response to injury. In this study, we investigated cell viability in three ex vivo OSC models of SCI: stab injury, transection injury and contusion injury. Injury was inflicted in postnatal day 4 rat spinal cord slices. Stab injury was performed using a needle on transverse slices of spinal cord. Transection injury was performed on longitudinal slices of spinal cord using a double blade technique. Contusion injury was performed on longitudinal slices of spinal cord using an Infinite Horizon impactor device. At days 3 and 10 post‐injury, viability was measured using dual staining for propidium iodide and fluorescein diacetate. In all ex vivo SCI models, the slices showed more live cells than dead cells over 10 days in culture, with higher cell viability in control slices compared with injured slices. Although no change in cell viability was observed between time‐points in stab‐ and contusion‐injured OSCs, a reduction in cell viability was observed over time in transection‐injured OSCs. Taken together, ex vivo SCI models are a useful and reliable research tool that reduces the cost and time involved in carrying out animal studies. The use of OSC models provides a simple way to study the cellular consequences following SCI, and they can also be used to investigate potential therapeutics regimes for the treatment of SCI.

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Section: Discussionsupporting

confidence: 92%

Cell viability in three ex vivo rat models of spinal cord injury

et al. 2018

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“…, ; Bastien et al . ). There is activation of microglia in the cord, even distal from the site, associated with tissue reorganization and impediment of functional recovery (Hansen et al .…”

Section: Classic Examples Of Neuroinflammation In the Context Of Centmentioning

confidence: 97%

Neuroinflammation: the devil is in the details

DiSabato

Quan

Godbout

2016

Journal of Neurochemistry

1,082

737

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There is significant interest in understanding inflammatory responses within the brain and spinal cord. Inflammatory responses that are centralized within the brain and spinal cord are generally referred to as “neuroinflammatory”. Aspects of neuroinflammation vary within the context of disease, injury, infection or stress. The context, course, and duration of these inflammatory responses are all critical aspects in the understanding of these processes and their corresponding physiological, biochemical and behavioral consequences. Microglia, innate immune cells of the central nervous system (CNS), play key roles in mediating these neuroinflammatory responses. Because the connotation of neuroinflammation is inherently negative and maladaptive, the majority of research focus is on the pathological aspects of neuroinflammation. There are, however, several degrees of neuroinflammatory responses, some of which are positive. In many circumstances including CNS injury, there is a balance of inflammatory and intrinsic repair processes that influences functional recovery. In addition, there are several other examples where communication between the brain and immune system involves neuroinflammatory processes that are beneficial and adaptive. The purpose of this review is to distinguish different variations of neuroinflammation in a context-specific manner and detail both positive and negative aspects of neuroinflammatory processes.

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“…Using mRNA isolated from 1d post-injection spinal cords, quantitative real-time PCR revealed that LPS with or without iron significantly increased transcription of inducible nitric oxide synthase (iNOS, ~400-fold; Fig 12A), tumor necrosis factor alpha (TNFα, ~6-fold; Fig 11B), interleukin-1 alpha (IL-1α, ~20-fold; Fig 12C) and interleukin-1β (~5-fold; not shown), all factors that contribute to neuron and/or OL toxicity (Fig. 12A–C; Li et al, 2005 & 2008; Bastien et al, 2015). Cultured microglia were similarly treated to examine direct effects of LPS and iron.…”

Section: Resultsmentioning

confidence: 99%

Intraspinal TLR4 activation promotes iron storage but does not protect neurons or oligodendrocytes from progressive iron-mediated damage

Goldstein

Church

Pukos

et al. 2017

Experimental Neurology

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Iron is essential for basic cellular functions but in excess is highly toxic. For this reason, free iron and iron storage are controlled in the periphery by elaborate regulatory mechanisms. In contrast, iron regulation in the central nervous system (CNS) is not well defined. Given that excess iron is present after trauma, hemorrhagic stroke and neurodegeneration, understanding normal iron regulation and promoting iron uptake in CNS pathology is crucial. Peripherally, toll-like receptor 4 (TLR4) activation promotes iron sequestration by macrophages. Notably, iron-rich sites of CNS pathology typically contain TLR4 agonists, which may promote iron uptake. Indeed, our recent work showed impaired iron storage after acute spinal cord injury in mice with TLR4 deficiency. Here we used a reductionist model to ask if TLR4 activation in the CNS stimulates iron uptake and promotes neuroprotection from iron-induced toxicity. For this, we measured the ability of microglia/macrophages to sequester exogenous iron and prevent pathology with and without concomitant intraspinal TLR4 activation. Results show that, similar to the periphery, activating intraspinal TLR4 via focal LPS injection increased mRNA encoding iron uptake and storage proteins and promoted iron sequestration into ferritin-expressing macrophages. However, this did not prevent oligodendrocyte and neuron loss. Moreover, replacement of oligodendrocytes by progenitor cells – a normally robust response to in vivo macrophage TLR4 activation – was significantly reduced if iron was present concomitant with TLR4 activation. Thus, while TLR4 signaling promotes CNS iron uptake, future work needs to determine ways to enhance iron removal without blocking the reparative effects of innate immune receptor signaling.

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IL-1 Gene Deletion Protects Oligodendrocytes after Spinal Cord Injury through Upregulation of the Survival Factor Tox3

Cited by 59 publications

References 63 publications

Cell viability in three ex vivo rat models of spinal cord injury

Cell viability in three ex vivo rat models of spinal cord injury

Neuroinflammation: the devil is in the details

Intraspinal TLR4 activation promotes iron storage but does not protect neurons or oligodendrocytes from progressive iron-mediated damage

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