Mobilisation of the splenic monocyte reservoir and peripheral CX3CR1 deficiency adversely affects recovery from spinal cord injury

Blomster, Linda V.; Brennan, Faith H.; Lao, Hong W.; Harle, David W.; Harvey, Alan R.; Ruitenberg, Marc J.

doi:10.1016/j.expneurol.2013.05.002

Cited by 88 publications

(97 citation statements)

References 61 publications

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“…We confirmed the effect of clodronate liposome by demonstrating that F4/80 + cells were visibly decreased in the spleen, which was reported as the main source of macrophages acutely after SCI (Blomster et al, 2013) (data not shown). Accordingly, CD11b + cells at the injury site were significantly reduced at both 7 and 14 days after SCI and this was associated with a significant reduction in the density of fibroblasts present at the injury site at both time points (Fig.…”

Section: Resultssupporting

confidence: 81%

Hematogenous macrophage depletion reduces the fibrotic scar and increases axonal growth after spinal cord injury

Zhu

Soderblom

Krishnan

et al. 2015

Neurobiology of Disease

168

180

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Spinal cord injury (SCI) leads to formation of a fibrotic scar that is inhibitory to axon regeneration. Recent evidence indicates that the fibrotic scar is formed by perivascular fibroblasts, but the mechanism by which they are recruited to the injury site is unknown. Using bone marrow transplantation in mouse model of spinal cord injury, we show that fibroblasts in the fibrotic scar are associated with hematogenous macrophages rather than microglia, which are limited to the surrounding astroglial scar. Depletion of hematogenous macrophages results in reduced fibroblast density and basal lamina formation that is associated with increased axonal growth in the fibrotic scar. Cytokine gene expression analysis after macrophage depletion indicates that decreased Tnfsf8, Tnfsf13 (Tumor necrosis factor superfamily members) and increased BMP1-7 (Bone Morphogenetic Proteins) expression may serve as anti-fibrotic mechanisms. Our study demonstrates that hematogenous macrophages are necessary for fibrotic scar formation and macrophage depletion results in changes in multiple cytokines that make the injury site less fibrotic and more conducive to axonal growth.

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Section: Resultssupporting

confidence: 81%

Hematogenous macrophage depletion reduces the fibrotic scar and increases axonal growth after spinal cord injury

Zhu

Soderblom

Krishnan

et al. 2015

Neurobiology of Disease

168

180

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“…A follow up study showed, however, an impaired locomotor function associated with an increase in infiltrating M/l cells when assessed at 42 days post-injury. 44 The results obtained in our study allow the proposal of a unifying interpretation of the literature data, highlighting a dual role for CX3CL1 and its receptor regulating microglial function at different time-points after acute brain injury. We report that the loss of CX3CL1:CX3CR1 interaction is associated with a different neuroinflammatory response in TBI, mediated by M/l.…”

Section: Discussionmentioning

confidence: 83%

Fractalkine Receptor Deficiency Is Associated with Early Protection but Late Worsening of Outcome following Brain Trauma in Mice

Zanier

Marchesi

Ortolano

et al. 2016

Journal of Neurotrauma

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An impaired ability to regulate microglia activation by fractalkine (CX3CL1) leads to microglia chronic sub-activation. How this condition affects outcome after acute brain injury is still debated, with studies showing contrasting results depending on the timing and the brain pathology. Here, we investigated the early and delayed consequences of fractalkine receptor (CX3CR1) deletion on neurological outcome and on the phenotypical features of the myeloid cells present in the lesions of mice with traumatic brain injury (TBI). Wild type (WT) and CX3CR1 -/-C57Bl/6 mice were subjected to sham or controlled cortical impact brain injury. Outcome was assessed at 4 days and 5 weeks after TBI by neuroscore, neuronal count, and terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) staining. Compared with WT mice, CX3CR1 -/-TBI mice showed a significant reduction of sensorimotor deficits and lower cellular damage in the injured cortex 4 days post-TBI. Conversely, at 5 weeks, they showed a worsening of sensorimotor deficits and pericontusional cell death. Microglia (M) and macrophage (l) activation and polarization were assessed by quantitative immunohistochemistry for CD11b, CD68, Ym1, and inducible nitric oxide synthase (iNOS)-markers of M/l activation, phagocytosis, M2, and M1 phenotypes, respectively. Morphological analysis revealed a decreased area and perimeter of CD11b + cells in CX3CR1 -/-mice at 4 days post-TBI, whereas, at 5 weeks, both parameters were significantly higher, compared with WT mice. At 4 days, CX3CR1 -/-mice showed significantly decreased CD68 and iNOS immunoreactivity, while at 5 weeks post-injury, they showed a selective increase of iNOS. Gene expression on CD11b + sorted cells revealed an increase of interleukin 10 and insulin-like growth factor 1 (IGF1) at 1 day and a decrease of IGF1 4 days and 5 weeks post-TBI in CX3CR1 -/-, compared with WT mice. These data show an early protection followed by a chronic exacerbation of TBI outcome in the absence of CX3CR1. Thus, longitudinal effects of myeloid cell manipulation at different stages of pathology should be investigated to understand how and when their modulation may offer therapeutic chances.

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“…Cx 3 cr1 gfp/ þ male recipient mice (6-9 months of age) 49 were sublethally irradiated with two doses of 5 Gy delivered 14 h apart and their immune system rescued via BM transplantation from either wild-type (control) or p110d D910A/D910A donors, 3-4 h after the second dose of irradiation 50 . In the latter group, expression of the kinase-dead form of PI3Kd was restricted to the peripheral immune compartment only, thereby allowing for the assessment of leukocyte recruitment following ischaemic stroke.…”

Section: Article Nature Communications | Doi: 101038/ncomms4450mentioning

confidence: 99%

PI3Kδ inhibition reduces TNF secretion and neuroinflammation in a mouse cerebral stroke model

et al. 2014

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Stroke is a major cause of death worldwide and the leading cause of permanent disability. Although reperfusion is currently used as treatment, the restoration of blood flow following ischaemia elicits a profound inflammatory response mediated by proinflammatory cytokines such as tumour necrosis factor (TNF), exacerbating tissue damage and worsening the outcomes for stroke patients. Phosphoinositide 3-kinase delta (PI3Kd) controls intracellular TNF trafficking in macrophages and therefore represents a prospective target to limit neuroinflammation. Here we show that PI3Kd inhibition confers protection in ischaemia/ reperfusion models of stroke. In vitro, restoration of glucose supply following an episode of glucose deprivation potentiates TNF secretion from primary microglia-an effect that is sensitive to PI3Kd inhibition. In vivo, transient middle cerebral artery occlusion and reperfusion in kinase-dead PI3Kd (p110d D910A/D910A ) or wild-type mice pre-or post-treated with the PI3Kd inhibitor CAL-101, leads to reduced TNF levels, decreased leukocyte infiltration, reduced infarct size and improved functional outcome. These data identify PI3Kd as a potential therapeutic target in ischaemic stroke.

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Mobilisation of the splenic monocyte reservoir and peripheral CX3CR1 deficiency adversely affects recovery from spinal cord injury

Cited by 88 publications

References 61 publications

Hematogenous macrophage depletion reduces the fibrotic scar and increases axonal growth after spinal cord injury

Hematogenous macrophage depletion reduces the fibrotic scar and increases axonal growth after spinal cord injury

Fractalkine Receptor Deficiency Is Associated with Early Protection but Late Worsening of Outcome following Brain Trauma in Mice

PI3Kδ inhibition reduces TNF secretion and neuroinflammation in a mouse cerebral stroke model

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