Control of microglial neurotoxicity by the fractalkine receptor

Cardona, Astrid E.; Pioro, Erik P.; Sasse, Margaret E.; Kostenko, Volodymyr; Cardona, Sandra M.; Dijkstra, Ineke M.; Huang, De Ren; Kidd, Grahame J.; Dombrowski, Stephen; Dutta, Ranjan; Lee, Jar Chi; Cook, Donald N.; Jung, Steffen; Lira, Sérgio A.; Littman, Dan R.; Ransohoff, Richard M.

doi:10.1038/nn1715

Cited by 1,347 publications

(1,384 citation statements)

References 37 publications

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“…Dénes et al demonstrated that there were no significant changes in the ischemic brain damage between Cx3cr1 GFP/+ and wild type mice, and Saederup et al showed that monocyte/macrophage recruitment after thioglycollate‐induced peritonitis was not significantly changed between Cx3cr1 GFP/+ Ccr2 RFP/+ and wild type mice (Dénes et al, 2008; Saederup et al, 2010). Moreover, we showed that Cx3cr1‐GFP+ and Ccr2‐RFP+ cells overlapped completely with Iba1, a marker expressed in both resident microglia and blood‐derived macrophages, as reported previously (Cardona et al, 2006). Thus, we believe that this strain of mice can be used to investigate the contribution of resident microglia and blood‐derived macrophages after HI without influence of the transgene expression.…”

Section: Discussionsupporting

confidence: 89%

Resident microglia, rather than blood‐derived macrophages, contribute to the earlier and more pronounced inflammatory reaction in the immature compared with the adult hippocampus after hypoxia‐ischemia

Umekawa

Osman

Han

et al. 2015

Glia

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The mechanisms of neuronal injury after hypoxia–ischemia (HI) are different in the immature and the adult brain, but microglia activation has not been compared. The purpose of this study was to phenotype resident microglia and blood‐derived macrophages in the hippocampus after HI in neonatal (postnatal day 9, P9) or adult (3 months of age, 3mo) mice. Unilateral brain injury after HI was induced in Cx3cr1GFP/+Ccr2RFP/+ male mice on P9 (n = 34) or at 3mo (n = 53) using the Vannucci model. Resident microglia (Cx3cr1‐GFP+) proliferated and were activated earlier after HI in the P9 (1–3 days) than that in the 3mo hippocampus, but remained longer in the adult brain (3–7 days). Blood‐derived macrophages (Ccr2‐RFP+) peaked 3 days after HI in both immature (P9) and adult (3mo) hippocampi but were twice as frequent in adult brains, 41% vs. 21% of all microglia/macrophages. CCL2 expression was three times higher in the P9 hippocampi, indicating that the proinflammatory response was more pronounced in the immature brain after HI. This corresponded well with the higher numbers of galectin‐3‐positive resident microglia in the P9 hippocampi, but did not correlate with CD16/32‐ or CD206‐positive resident microglia or blood‐derived macrophages. In conclusion, resident microglia, rather than infiltrating blood‐derived macrophages, proliferate and are activated earlier in the immature than in the adult brain, but remain increased longer in the adult brain. The inflammatory response is more pronounced in the immature brain, and this correlate well with galectin‐3 expression in resident microglia. GLIA 2015;63:2220–2230

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Section: Discussionsupporting

confidence: 89%

Resident microglia, rather than blood‐derived macrophages, contribute to the earlier and more pronounced inflammatory reaction in the immature compared with the adult hippocampus after hypoxia‐ischemia

Umekawa

Osman

Han

et al. 2015

Glia

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“…Astrocytes expressing GFAP or glutamine synthetase as well as neurons identified by NeuN expression were not positive to GFP in intact mice and in mice subjected to MCAo (not shown), confirming previous observations by others (Cardona et al, 2006).…”

Section: Gfp/cd45-staining Reveals Less-infiltrating Leukocytes In Thsupporting

confidence: 91%

“…Absence of fractalkine receptor in CX3CR1À/À mice was reported to cause cell-autonomous microglial neurotoxicity after systemic LPS treatment in a toxic model of Parkinson's disease and a transgenic model of amyotrophic lateral sclerosis (Cardona et al, 2006). Furthermore, CX3CR1À/À microglia were shown to accumulate and promote retinal degeneration (Combadiere et al, 2007).…”

Section: Discussionmentioning

confidence: 99%

“…In the brain, neurons constitutively express high levels of the chemokine CX3CL1, which has been suggested to be responsible for sustaining normal microglial activity through interaction with microglial CX3CR1 (Biber et al, 2007;Hanisch and Kettenmann, 2007). It was recently shown that CX3CR1 deficiency dysregulates microglial responses, resulting in microglial neurotoxicity in vivo in three different disease models using transgenic mice (Cardona et al, 2006), in which the cx3cr1 gene was replaced by a green fluorescent protein (GFP) reporter gene (Jung et al, 2000). Unlike peritoneal macrophages, microglia isolated from homozygote (CX3CR1À/À) mice expressed significantly more IL-1b in response to activation by lipopolysaccharides (LPS) than microglia derived from heterozygote (CX3CR1 + /À) mice (Cardona et al, 2006).…”

Section: Introductionmentioning

confidence: 99%

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Role of CX3CR1 (Fractalkine Receptor) in Brain Damage and Inflammation Induced by Focal Cerebral Ischemia in Mouse

Dénes

Ferenczi

Halász

et al. 2008

J Cereb Blood Flow Metab

252

220

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CX3CR1 (fractalkine receptor) is important for sustaining normal microglial activity in the brain. Lack of CX3CR1 reportedly results in neurotoxic microglial phenotype in disease models. The objective of this study was to test the hypothesis that the absence of CX3CR1 worsens the outcome in cerebral ischemia. We observed significantly smaller (56%) infarcts and blood-brain barrier damage in CX3CR1-deficient (CX3CR1À/À) animals compared with CX3CR1 + /À and wild-type mice after transient occlusion of the middle cerebral artery (MCAo). Functional recovery of CX3CR1À/À animals was enhanced, while less number of apoptotic cells and infiltrating leukocytes were found in the ipsilateral hemisphere. Expression of IL-1b mRNA, protein, and interleukin (IL)-1Ra and tumor necrosis factor (TNF)-a mRNAs was lower in CX3CR1À/À mice, whereas no difference was observed in the number of IL-1b-expressing microglia or plasma IL-1b concentration. We observed early IL-1b expression in astrocytes in vivo after MCAo and after oxygen-glucose deprivation in vitro, which might contribute to the ischemic damage. Our findings indicate that lack of CX3CR1 does not result in microglial neurotoxicity after MCAo, but rather significantly reduces ischemic damage and inflammation. Reduced IL-1b and TNFa expression as well as decreased leukocyte infiltration might be involved in the development of smaller infarcts in CX3CR1À/À animals.

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“…Previous reports have shown that IL-1␤ develops neurotoxic properties in the brain. 5,13,32 However, in the retina IL-1␤ was shown to inhibit ganglion cell death, 6 and IL-1␤ substitution saved photoreceptors in light-induced models 7 and genetic retinal degeneration. 8 Here, we show that IL-1␤ is significantly induced in the light-induced model in albino rats ( Figure 4D) and in albino mice ( Figure 5B).…”

Section: Discussionmentioning

confidence: 99%

Interleukin-1β Inhibition Prevents Choroidal Neovascularization and Does Not Exacerbate Photoreceptor Degeneration

Lavalette

Raoul

Houssier

et al. 2011

The American Journal of Pathology

124

106

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Control of microglial neurotoxicity by the fractalkine receptor

Cited by 1,347 publications

References 37 publications

Resident microglia, rather than blood‐derived macrophages, contribute to the earlier and more pronounced inflammatory reaction in the immature compared with the adult hippocampus after hypoxia‐ischemia

Resident microglia, rather than blood‐derived macrophages, contribute to the earlier and more pronounced inflammatory reaction in the immature compared with the adult hippocampus after hypoxia‐ischemia

Role of CX3CR1 (Fractalkine Receptor) in Brain Damage and Inflammation Induced by Focal Cerebral Ischemia in Mouse

Interleukin-1β Inhibition Prevents Choroidal Neovascularization and Does Not Exacerbate Photoreceptor Degeneration

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