Time-dependent effects of CX3CR1 in a mouse model of mild traumatic brain injury

“M1 microglia are generally considered pro-inflammatory whereas, M2 microglia are generally anti-inflammatory [29 – 34].”

“M1 microglia are generally considered pro-inflammatory whereas, M2 microglia are generally anti-inflammatory [29–34].”

“Conversely, monocytes of the subset Ly6C low /CX3CR1 high are CCR2 deficient and are dependent on CX3CR1 for recruitment [51 – 53].”

“All cell counts were obtained using the Optical Fractionator method of unbiased stereological counting techniques [39].”

“Indeed, deleting CX3CR1 [4] exacerbates microglial neurotoxicity induced by systemic inflammation in rodent models of Parkinson’s disease and amyotrophic lateral sclerosis [5].”

“For example, in a model of myocardial infarction, tissue repair requires recruitment of Ly6C and then Ly6C monocytes [53].”

“Ly6C monocytes are proteolitic, degrade injured tissue, and give rise to M1 macrophages in vivo [35, 56].”

“CX3CR1 monocytes may differentiate from Ly6C monocytes in tissue and thus may not require CX3CR1 for recruitment [54, 55].”

“Antibodies and dilutions were as follows: rat CD11b (Serotec, Raleigh, NC, USA; 1:500); mouse CD68 (Serotec; 1:200); rabbit YM1 (Stem cell technology, Vancouver, BC, Canada; 1:400); rat Marco (Serotec; 1:500); mouse NeuN (Millipore, Temecula, CA, USA; 1:1000).”

“Indeed, deleting CX3CR1 [4] exacerbates microglial neurotoxicity induced by systemic inflammation in rodent models of Parkinson’s disease and amyotrophic lateral sclerosis [5].”

“Data from some models of chronic neuronal injury suggest that CX3CR1 is protective because the absence of this receptor increases microglia activity and is associated with less favorable outcome [8, 12–16].”

“A consensus based on recent evidence considers neuroinflammation as an important secondary mechanism that plays a role in delaying injury after TBI [1–3].”

“M1 microglia are generally considered pro-inflammatory whereas, M2 microglia are generally anti-inflammatory [29–34].”

“Because TBI involves infiltration of peripheral blood monocytes into the brain [44], we first isolated mononuclear cells from WT and CX3CR1 mice at 15 or 30 days post-TBI and analyzed them with flow cytometry (Fig.”

“Conversely, monocytes of the subset Ly6C/CX3CR1 are CCR2 deficient and are dependent on CX3CR1 for recruitment [51–53].”

“M1 microglia are generally considered pro-inflammatory whereas, M2 microglia are generally anti-inflammatory [29 – 34].”

“Data from some models of chronic neuronal injury suggest that CX3CR1 is protective because the absence of this receptor increases microglia activity and is associated with less favorable outcome [8, 12–16].”

“For instance, in a model of Alzheimer ’ s disease (AD), CX3CR1-deficient microglia from mice overexpressing hTau have increased hyperphosphorylated tau and more toxicity, as has been observed in other animal ’ s disease models [5, 17 – 20].”

“Spatial learning was evaluated using the Morris water maze (MWM) task as previously described [40].”

“Antibodies and dilutions were as follows: rat CD11b (Serotec, Raleigh, NC, USA; 1:500); mouse CD68 (Serotec; 1:200); rabbit YM1 (Stem cell technology, Vancouver, BC, Canada; 1:400); rat Marco (Serotec; 1:500); mouse NeuN (Millipore, Temecula, CA, USA; 1:1000).”

“On the other hand, in 3x-Tg AD mice, which reproduces both Aβ and tau pathologies, deleting CX3CR1 prevents neuronal loss and microglial migration without affecting amyloid deposition [21].”

“Finally, other reports indicate that CX3CR1 deficiency attenuates amyloid deposition in AD mouse models characterized by extensive plaque deposition [18, 22].”

“In experimental models of spinal cord injury and focal cerebral ischemia, tissue damage is attenuated and function recovers earlier following injury in CX3CR1-deficient mice, effects attributed to reduced recruitment and/or activation of microglia/macrophages [23, 24, 57, 58].”

“Both beneficial and detrimental effects of CX3CR1 deficiency are associated with microglia activation [9 – 11].”

“Although a shift in microglia phenotype between the acute and chronic phase of TBI has recently been reported [49], we extend these observations by identifying CX3CR1 as a possible regulator of this microglia/macrophage phenotype switch following mild TBI.”

“Both beneficial and detrimental effects of CX3CR1 deficiency are associated with microglia activation [9 – 11].”

“M1 microglia are generally considered pro-inflammatory whereas, M2 microglia are generally anti-inflammatory [29–34].”

“CX3CL1 also protects against excitotoxicity through the activation of the ERK1/2 and PI3K/Akt pathways [7, 8].”

“Data from some models of chronic neuronal injury suggest that CX3CR1 is protective because the absence of this receptor increases microglia activity and is associated with less favorable outcome [8, 12–16].”

“[41, 42], and cellular pellets resuspended in cell staining buffer (Biolegend, San Diego, CA, USA).”

“In addition, CX3CR1 microglia exacerbate cell-autonomous microglial neurotoxicity induced by lipopolysaccharide (LPS), suggesting that fractalkine signaling is important for limiting microglia toxicity [5, 6].”

“Ly6C monocytes are proteolitic, degrade injured tissue, and give rise to M1 macrophages in vivo [35, 56].”

“A consensus based on recent evidence considers neuroinflammation as an important secondary mechanism that plays a role in delaying injury after TBI [1 – 3].”

“In experimental models of spinal cord injury and focal cerebral ischemia, tissue damage is attenuated and function recovers earlier following injury in CX3CR1-deficient mice, effects attributed to reduced recruitment and/or activation of microglia/macrophages [23, 24, 57, 58].”

“For instance, in a model of Alzheimer ’ s disease (AD), CX3CR1-deficient microglia from mice overexpressing hTau have increased hyperphosphorylated tau and more toxicity, as has been observed in other animal ’ s disease models [5, 17 – 20].”

“M1 microglia are generally considered pro-inflammatory whereas, M2 microglia are generally anti-inflammatory [29–34].”

“[50] using CX3CR1 CCR2 reporter mice have demonstrated a broad spectrum of M1-M2 polarization mRNA gene expression following TBI, with changes occurring primarily during the first 48 h.”

“Data from some models of chronic neuronal injury suggest that CX3CR1 is protective because the absence of this receptor increases microglia activity and is associated with less favorable outcome [8, 12 – 16].”

“Previous studies have reported that these parameters produce a mild injury [36, 37].”

“[23] showed that abolishing CX3CR1 reduces accumulation of CD11b/Ly6C/iNOS monocytes, which confers neuroprotection and promotes recovery of function at early time points after spinal cord injury.”

“In experimental models of spinal cord injury and focal cerebral ischemia, tissue damage is attenuated and function recovers earlier following injury in CX3CR1-deficient mice, effects attributed to reduced recruitment and/or activation of microglia/macrophages [23, 24, 57, 58].”

“Similarly, CX3CR1 mice are protected from the middle cerebral artery occlusion, with smaller infarct size at early time points after injury, which is associated with an M2 microglial phenotype [26].”

“Previous studies have reported that these parameters produce a mild injury [36, 37].”

“Fluoro-Jade B staining was performed according to Kubova et al. [38].”

“For instance, in a model of cerebral ischemia and spinal cord injury, CX3CR1 mice showed neuroprotection and improved functional recovery [23–26].”

“For instance, in a model of Alzheimer’s disease (AD), CX3CR1-deficient microglia from mice overexpressing hTau have increased hyperphosphorylated tau and more toxicity, as has been observed in other animal’s disease models [5, 17–20].”

“Intraventricular infusion of mesenchymal stem cells after TBI induces early and lasting acquisition of a protective M2 microglial phenotype that is associated with reduced CD68 immunoreactivity [46].”

“Although microglial phagocytosis of dead or dying neurons can be beneficial by preventing the release of pro-inflammatory molecules, under some conditions, such as inflammation, microglia also phagocytize viable neurons, thus contributing to cell death [45].”

“CX3CL1 also protects against excitotoxicity through the activation of the ERK1/2 and PI3K/Akt pathways [7, 8].”

“[41, 42], and cellular pellets resuspended in cell staining buffer (Biolegend, San Diego, CA, USA).”

“A consensus based on recent evidence considers neuroinflammation as an important secondary mechanism that plays a role in delaying injury after TBI [1–3].”

“Data from some models of chronic neuronal injury suggest that CX3CR1 is protective because the absence of this receptor increases microglia activity and is associated with less favorable outcome [8, 12–16].”

“Cells were then stained with Ki67-V450 (Clone B56) in permeabilization buffer for 20 min, washed, resuspended in 2 % PFA, and acquired on an LSR-II [43].”

“CX3CR1 monocytes may differentiate from Ly6C monocytes in tissue and thus may not require CX3CR1 for recruitment [54, 55].”

“CX3CL1 levels increase in the cerebrospinal fluid and in the brain of patients with head trauma, and increased CX3CL1/CX3CR1 is associated with better clinical outcome [27, 28].”

“The activity of macrophages appears to be a potential therapeutic target in different TBI settings in adult, but not young, rodents (Febinger et al., 2015; Erturk et al., 2016; Hanlon et al., 2016; Zanier et al., 2016; Chhor et al., 2017; Saber et al., 2017).”

“…2014 Mouse C57Bl/6 ♂ CCI, moderate 3 mm dpi: 3, 7 M1: CD11b, TNF-α, CD68, CD86, IL-1β M2a/c: Ym1, Arg-1, CD206, SOCS3, IL-10 Mixed expression of M1 and M2 marker mRNA M1: N at 3 + 7 dpi M2: N Ym1, Arg-1, SOCS3 at 3 dpi Febinger et al., 2015 Mouse CX3CR1−/− CX3CR1+/+ ♂ CCI, mild 3 mm dpi: 7, 15,…”

“, 2016), whereas time-dependent effects were found concerning cognitive dysfunction after mild brain trauma (Febinger et al., 2015).”