Knockout of fractalkine receptor Cx3cr1 does not alter disease or microglial activation in prion-infected mice

Striebel, James F.; Race, Brent; Carroll, James A.; Phillips, Katie; Chesebro, Bruce

doi:10.1099/jgv.0.000442

Cited by 12 publications

(10 citation statements)

References 28 publications

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“…However, we found that the activation of the presumed resident microglia (branched, parenchymal Iba1+ cells) remained unchanged in terms of morphology and Iba1 mRNA levels with loss of Cx3cr1. A similar lack of change in microglia activation in Cx3cr1 knockouts was also observed in other disease models, such as prion-infected mice (Striebel et al, 2016). Activated microglia can secrete pro-inflammatory cytokines like Il1β (Patterson, 2015), and loss of Cx3cr1 has been shown to elevate levels of the pro-inflammatory cytokine Il1β (Cardona et al, 2006) In diabetic retinopathy, only a few genes associated with inflammation are significantly upregulated in Cx3cr1 knockout retina, including Il1β (Cardona et al, 2015).…”

Section: Discussionsupporting

confidence: 72%

“…Consistent with this, we also found increased levels of expression of the ligand for Ccr2, Ccl2, which can promote infiltration (Sennlaub et al, 2013). Ccl2 was also found to be increased in brains from prion-infected Cx3cr1 knockout vs. wild type C57Bl6/J mice (Striebel et al, 2016). Increased CCR2+ macrophage infiltration on a Cx3cr1 null background is consistent with what has been observed in age and light damage models of subretinal inflammation that clearly showed a pathogenic role for these infiltrating macrophages (Sennlaub et al, 2013).…”

Section: Discussionmentioning

confidence: 99%

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Loss of Fractalkine Signaling Exacerbates Axon Transport Dysfunction in a Chronic Model of Glaucoma

et al. 2016

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Neurodegeneration in glaucoma results in decline and loss of retinal ganglion cells (RGCs), and is associated with activation of myeloid cells such as microglia and macrophages. The chemokine fractalkine (FKN or Cx3cl1) mediates communication from neurons to myeloid cells. Signaling through its receptor Cx3cr1 has been implicated in multiple neurodegenerative diseases, but the effects on neuronal pathology are variable. Since it is unknown how FKN-mediated crosstalk influences RGC degeneration in glaucoma, we assessed this in a chronic mouse model, DBA/2J. We analyzed a DBA/2J substrain deficient in Cx3cr1, and compared compartmentalized RGC degeneration and myeloid cell responses to those in standard DBA/2J mice. We found that loss of FKN signaling exacerbates axon transport dysfunction, an early event in neurodegeneration, with a significant increase in RGCs with somal accumulation of the axonal protein phosphorylated neurofilament, and reduced retinal expression of genes involved in axon transport, Kif1b, and Atp8a2. There was no change in the loss of Brn3-positive RGCs, and no difference in the extent of damage to the proximal optic nerve, suggesting that the loss of fractalkine signaling primarily affects axon transport. Since Cx3cr1 is specifically expressed in myeloid cells, we assessed changes in retinal microglial number and activation, changes in gene expression, and the extent of macrophage infiltration. We found that loss of fractalkine signaling led to innate immune changes within the retina, including increased infiltration of peripheral macrophages and upregulated nitric oxide synthase-2 (Nos-2) expression in myeloid cells, which contributes to the production of NO and can promote axon transport deficits. In contrast, resident retinal microglia appeared unchanged either in number, morphology, or expression of the myeloid activation marker ionized calcium binding adaptor molecule 1 (Iba1). There was also no significant increase in the proinflammatory gene interleukin 1 beta (Il1β). We conclude that loss of fractalkine signaling causes a selective worsening of axon transport dysfunction in RGCs, which is linked to enhanced Nos-2 expression in myeloid cells. Our findings suggest that distinct mechanisms may contribute to different aspects of RGC decline in glaucoma, with axonal transport selectively altered after loss of Cx3cr1 in microglia and/or macrophages.

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Section: Discussionsupporting

confidence: 72%

Section: Discussionmentioning

confidence: 99%

Loss of Fractalkine Signaling Exacerbates Axon Transport Dysfunction in a Chronic Model of Glaucoma

et al. 2016

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“…The role of CX3CR1 in prion disease has been studied by two independent groups. While one group demonstrated that lack of CX3CR1 led to modest but significant reductions in incubation time (82), suggesting a neuroprotective role of CX3CR1 signaling in prion pathogenesis, the other group failed to find any difference in disease onset, duration of disease, or pathology of disease between the Cx3cr1 -/-mice and WT controls (83). The discrepancy between these two studies may be due to the distinct mouse strains or different experimental protocols used in each study.…”

Section: R E V I E W S E R I E S : G L I a A N D N E U R O D E G E N mentioning

confidence: 46%

Microglia in prion diseases

Aguzzi

Zhu

2017

Journal of Clinical Investigation

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“…Regiondependent significantly altered expression is found in both sCJD subtypes compared to controls. AU arbitrary units The activation of microglial is a trademark of the neuroimmunological response in prion disease [62]. Recent report demonstrated the suggestive role of microglia during the clearance of cofilin aggregation [53].…”

Section: Dense Accumulation Of F-actin and Activation Of Microgliamentioning

confidence: 99%

Cytoskeleton-Associated Risk Modifiers Involved in Early and Rapid Progression of Sporadic Creutzfeldt-Jakob Disease

et al. 2017

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A high priority in the prion field is to identify pre-symptomatic events and associated profile of molecular changes. In this study, we demonstrate the pre-symptomatic dysregulation of cytoskeleton assembly and its associated cofilin-1 pathway in strain and brain region-specific manners in MM1 and VV2 subtype-specific Creutzfeldt-Jakob disease at clinical and pre-clinical stage. At physiological level, PrP interaction with cofilin-1 and phosphorylated form of cofilin (p-cofilin(Ser3)) was investigated in primary cultures of mouse cortex neurons (PCNs) of PrP wild-type and knockout mice (PrP). Short-interfering RNA downregulation of active form of cofilin-1 resulted in the redistribution/downregulation of PrP, increase of activated form of microglia, accumulation of dense form of F-actin, and upregulation of p-cofilin(Ser3). This upregulated p-cofilin(Ser3) showed redistribution of expression predominantly in the activated form of microglia in PCNs. At pathological level, cofilin-1 expression was significantly altered in cortex and cerebellum in both humans and mice at pre-clinical stage and at early symptomatic clinical stage of the disease. Further, to better understand the possible mechanism of dysregulation of cofilin-1, we also demonstrated alterations in upstream regulators; LIM kinase isoform 1 (LIMK1), slingshot phosphatase isoform 1 (SSH1), RhoA-associated kinase (Rock2), and amyloid precursor protein (APP) in sporadic Creutzfeldt-Jakob disease MM1 mice and in human MM1 and VV2 frontal cortex and cerebellum samples. In conclusion, our findings demonstrated for the first time a key pre-clinical response of cofilin-1 and the associated pathway in prion disease.

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Knockout of fractalkine receptor Cx3cr1 does not alter disease or microglial activation in prion-infected mice

Cited by 12 publications

References 28 publications

Loss of Fractalkine Signaling Exacerbates Axon Transport Dysfunction in a Chronic Model of Glaucoma

Loss of Fractalkine Signaling Exacerbates Axon Transport Dysfunction in a Chronic Model of Glaucoma

Microglia in prion diseases

Cytoskeleton-Associated Risk Modifiers Involved in Early and Rapid Progression of Sporadic Creutzfeldt-Jakob Disease

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