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Cited by 110Traumatic Brain Injury and Neurovascular DisturbancesNeuroinflammation and Neurodegeneration MechanismsTraumatic Brain Injury Research

The DOI matches its Crossref record; 57 of the 58 references it cites were found in a registry or an index.

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

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Febinger, Heidi Y., Thomasy, Hannah E., Pavlova, Maria N., Ringgold, Kristyn M., Barf, Paulien R., George, Amrita M., Grillo, Jenna N., Bachstetter, Adam D., Garcia, Jenny A., Cardona, Astrid E., Opp, Mark R., Gemma, Carmelina·2015·Journal of Neuroinflammation
DOI 10.1186/s12974-015-0386-5PMC PMC4557842
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Abstract

BACKGROUND: Neuroinflammation is an important secondary mechanism that is a key mediator of the long-term consequences of neuronal injury that occur in traumatic brain injury (TBI). Microglia are highly plastic cells with dual roles in neuronal injury and recovery. Recent studies suggest that the chemokine fractalkine (CX3CL1, FKN) mediates neural/microglial interactions via its sole receptor CX3CR1. CX3CL1/CX3CR1 signaling modulates microglia activation, and depending upon the type and time of injury, either protects or exacerbates neurological diseases. METHODS: In this study, mice deficient in CX3CR1 were subjected to mild controlled cortical impact injury (CCI), a model of TBI. We evaluated the effects of genetic deletion of CX3CR1 on histopathology, cell death/survival, microglia activation, and cognitive function for 30 days post-injury. RESULTS: During the acute post-injury period (24 h-15 days), motor deficits, cell death, and neuronal cell loss were more profound in injured wild-type than in CX3CR1(-/-) mice. In contrast, during the chronic period of 30 days post-TBI, injured CX3CR1(-/-) mice exhibited greater cognitive dysfunction and increased neuronal death than wild-type mice. The protective and deleterious effects of CX3CR1 were associated with changes in microglia phenotypes; during the acute phase CX3CR1(-/-) mice showed a predominant anti-inflammatory M2 microglial response, with increased expression of Ym1, CD206, and TGFβ. In contrast, increased M1 phenotypic microglia markers, Marco, and CD68 were predominant at 30 days post-TBI. CONCLUSION: Collectively, these novel data demonstrate a time-dependent role for CX3CL1/CX3CR1 signaling after TBI and suggest that the acute and chronic responses to mild TBI are modulated in part by distinct microglia phenotypes.

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Fig. 1 Composite neuroscore (mean ± SEM). Evaluation of neuromotor function and recovery over a 30-day period. At 24 h post-TBI, injured WT mice (n = 3) demonstrated a significant decline in neuromotor function compared with sham WT (n = 4) and CX3CR1−/− injured mice (n = 4; two-way ANOVA, F (1, 9) **p = 0.001; **p = 0.001). At 7 days post-TBI, injured WT mice (n = 5) continued to demonstrate significant impairment than sham WT mice (n = 5; two-way ANOVA, F (1, 15) *p = 0.01). Injured CX3CR1−/− mice (n = 4) were not different from the injured WT mice (p > 0.05). A significant impairment in motor function performance was still present at 15 days post-injury in injured WT mice (n = 8) compared to sham WT mice (n = 8; two-way ANOVA, F (1, 15) **p = 0.001;). Injured CX3CR1−/− mice (n = 8) were not different from the injured WT mice (n = 8; p > 0.05). All injured mice (n = 5) recovered similarly at 30 days post-TBI. White bar = CX3CR1 sham WT. Green bar = CX3CR1 sham KO. Red Bar = CX3CR1 WT-TBI. Blue bar = CX3CR1 KO-TBI
Fig. 1 Composite neuroscore (mean ± SEM). Evaluation of neuromotor function and recovery over a 30-day period. At 24 h post-TBI, injured WT mice (n = 3) demonstrated a significant decline in neuromotor function compared with sham WT (n = 4) and CX3CR1−/− injured mice (n = 4; two-way ANOVA, F (1, 9) **p = 0.001; **p = 0.001). At 7 days post-TBI, injured WT mice (n = 5) continued to demonstrate significant impairment than sham WT mice (n = 5; two-way ANOVA, F (1, 15) *p = 0.01). Injured CX3CR1−/− mice (n = 4) were not different from the injured WT mice (p > 0.05). A significant impairment in motor function performance was still present at 15 days post-injury in injured WT mice (n = 8) compared to sham WT mice (n = 8; two-way ANOVA, F (1, 15) **p = 0.001;). Injured CX3CR1−/− mice (n = 8) were not different from the injured WT mice (n = 8; p > 0.05). All injured mice (n = 5) recovered similarly at 30 days post-TBI. White bar = CX3CR1 sham WT. Green bar = CX3CR1 sham KO. Red Bar = CX3CR1 WT-TBI. Blue bar = CX3CR1 KO-TBICC BY · PubMed Central
Fig. 2 Evaluation of behavioral analysis 30 days post-TBI. a In the open-field task, all mice traveled the same distance in the center zone compared to the perimeter zone. CX3CR1 WT-TBI spent less time in the perimeter zone of the open-field chamber compared to CX3CR1 KO-TBI (two-way ANOVA (F = 3, 72, **p = 0.01). Total distance traveled in the chamber was significantly different between CX3CR1 sham WT and CX3CR1 sham KO mice. Two-way ANOVA (F = 1, 36, **p = 0.001) and between shams and TBI groups two-way ANOVA (F = 1, 36, **p = 0.001). CX3CR1 sham WT (n = 10 white bar), CX3CR1 sham KO (n = 10 green bar), CX3CR1 WT-TBI (n = 10 red bar), and CX3CR1 KO-TBI (n = 10 blue bar) mice. b Rota-rod. CX3CR1 sham WT mice performed significantly better than CX3CR1 sham KO mice, over the 2 days of training (repeated measures ANOVA, *p = 0.5). No difference between injured groups was observed in the learning ability in the rota-rod task during the first day of training. On the second day of training (trials 5–8), CX3CR1 sham WT mice learned the rota-rod task as demonstrated by their ability to remain on the rod for longer periods compared to CX3CR1 WT-TBI (**p = 0.01). CX3CR1 KO-TBI mice showed a significantly worse performance than CX3CR1 WT-TBI wild-type (*p = 0.5). Neither the CX3CR1 KO-TBI nor the CX3CR1 WT-TBI mice showed significant improvement in motor coordination with training when compared to sham WT. CX3CR1 sham WT (n = 10; white open square). CX3CR1 WT-TBI (n = 10; red square). CX3CR1 sham KO (n = 10; green square). CX3CR1 KO-TBI (n = 10; blue squares). c–e Morris water maze. c Mean latency to escape from a pool to a hidden platform across training days. All groups spent more time in learning to find the platform compared to sham WT. CX3CR1 sham WT (n = 8; white bar). CX3CR1 WT-TBI (n = 9; red square). CX3CR1 sham KO (n = 8; green square). CX3CR1 KO-TBI (n = 9; blue squares). d A probe test was performed on day 8 to determine the number of pseudo platform crossings in the target quadrant. All TBI groups crossed less number of time the target quadrant zone when compared to CX3CR1 sham WT. CX3CR1 KO-TBI mice crossed the target quadrant less number of time than CX3CR1 sham KO and CX3CR1 WT-TBI. e No difference was observed in the average swim speed between groups. CX3CR1 sham WT (n = 8; white bar). CX3CR1 WT-TBI (n = 9; red square). CX3CR1 sham KO (n= 8; green square). CX3CR1 KO-TBI (n = 9; blue squares). All data are presented as mean ± SEM p < 0.01
Fig. 2 Evaluation of behavioral analysis 30 days post-TBI. a In the open-field task, all mice traveled the same distance in the center zone compared to the perimeter zone. CX3CR1 WT-TBI spent less time in the perimeter zone of the open-field chamber compared to CX3CR1 KO-TBI (two-way ANOVA (F = 3, 72, **p = 0.01). Total distance traveled in the chamber was significantly different between CX3CR1 sham WT and CX3CR1 sham KO mice. Two-way ANOVA (F = 1, 36, **p = 0.001) and between shams and TBI groups two-way ANOVA (F = 1, 36, **p = 0.001). CX3CR1 sham WT (n = 10 white bar), CX3CR1 sham KO (n = 10 green bar), CX3CR1 WT-TBI (n = 10 red bar), and CX3CR1 KO-TBI (n = 10 blue bar) mice. b Rota-rod. CX3CR1 sham WT mice performed significantly better than CX3CR1 sham KO mice, over the 2 days of training (repeated measures ANOVA, *p = 0.5). No difference between injured groups was observed in the learning ability in the rota-rod task during the first day of training. On the second day of training (trials 5–8), CX3CR1 sham WT mice learned the rota-rod task as demonstrated by their ability to remain on the rod for longer periods compared to CX3CR1 WT-TBI (**p = 0.01). CX3CR1 KO-TBI mice showed a significantly worse performance than CX3CR1 WT-TBI wild-type (*p = 0.5). Neither the CX3CR1 KO-TBI nor the CX3CR1 WT-TBI mice showed significant improvement in motor coordination with training when compared to sham WT. CX3CR1 sham WT (n = 10; white open square). CX3CR1 WT-TBI (n = 10; red square). CX3CR1 sham KO (n = 10; green square). CX3CR1 KO-TBI (n = 10; blue squares). c–e Morris water maze. c Mean latency to escape from a pool to a hidden platform across training days. All groups spent more time in learning to find the platform compared to sham WT. CX3CR1 sham WT (n = 8; white bar). CX3CR1 WT-TBI (n = 9; red square). CX3CR1 sham KO (n = 8; green square). CX3CR1 KO-TBI (n = 9; blue squares). d A probe test was performed on day 8 to determine the number of pseudo platform crossings in the target quadrant. All TBI groups crossed less number of time the target quadrant zone when compared to CX3CR1 sham WT. CX3CR1 KO-TBI mice crossed the target quadrant less number of time than CX3CR1 sham KO and CX3CR1 WT-TBI. e No difference was observed in the average swim speed between groups. CX3CR1 sham WT (n = 8; white bar). CX3CR1 WT-TBI (n = 9; red square). CX3CR1 sham KO (n= 8; green square). CX3CR1 KO-TBI (n = 9; blue squares). All data are presented as mean ± SEM p < 0.01CC BY · PubMed Central
Fig. 3 Quantification of neuronal loss at 15 and 30 days post-TBI. Left panel (a): unbiased stereology quantification showed a significant decrease in the number of Fluoro-Jade B+ cells in the ipsilateral cortex (F = 1, 10; *p = 0.001) of CX3CR1 KO-TBI mice (n = 3; blue bar) at 15 days post-TBI, when compared to CX3CR1 WT-TBI (n = 3; red bar). CX3CR1 sham WT (not detected), CX3CR1 sham KO (not detected). Fifteen days post-TBI, the decrease in the number of Fluoro-Jade B+ cells in CX3CR1 KO-TBI mice was associated with a significant increase in the number of NeuN+ cells (right pane (b); n = 3) compared to CX3CR1 WT-TBI (n = 3 **p = 0.001). Thirty days post-TBI CX3CR1 KO mice showed increased number of Fluoro-Jade B+ cells (n = 3; *p = 0.01) which was associated with decreased NeuN immunoreactivity (n = 5; **p = 0.001; mean ± SE (*WT vs CX3CR1−/− ± 15 vs 30 days). CX3CR1 sham WT (white bar), CX3CR1 sham KO (green bar), CX3CR1 WT-TBI (red bar), and CX3CR1 KO-TBI (blue bar). At 30 days, the number of NeuN+ cells was not determined (nd). Two-way ANOVA performed across genotype, treatment, and time point revealed a significant difference in the number of Fluoro-Jade and NeuN+ cells when compared between 15 and 30 days post-injury
Fig. 3 Quantification of neuronal loss at 15 and 30 days post-TBI. Left panel (a): unbiased stereology quantification showed a significant decrease in the number of Fluoro-Jade B+ cells in the ipsilateral cortex (F = 1, 10; *p = 0.001) of CX3CR1 KO-TBI mice (n = 3; blue bar) at 15 days post-TBI, when compared to CX3CR1 WT-TBI (n = 3; red bar). CX3CR1 sham WT (not detected), CX3CR1 sham KO (not detected). Fifteen days post-TBI, the decrease in the number of Fluoro-Jade B+ cells in CX3CR1 KO-TBI mice was associated with a significant increase in the number of NeuN+ cells (right pane (b); n = 3) compared to CX3CR1 WT-TBI (n = 3 **p = 0.001). Thirty days post-TBI CX3CR1 KO mice showed increased number of Fluoro-Jade B+ cells (n = 3; *p = 0.01) which was associated with decreased NeuN immunoreactivity (n = 5; **p = 0.001; mean ± SE (*WT vs CX3CR1−/− ± 15 vs 30 days). CX3CR1 sham WT (white bar), CX3CR1 sham KO (green bar), CX3CR1 WT-TBI (red bar), and CX3CR1 KO-TBI (blue bar). At 30 days, the number of NeuN+ cells was not determined (nd). Two-way ANOVA performed across genotype, treatment, and time point revealed a significant difference in the number of Fluoro-Jade and NeuN+ cells when compared between 15 and 30 days post-injuryCC BY · PubMed Central
Fig. 4 Increased microglial reaction after TBI. CX3CR1+/+ (WT; white bar) and CX3CR1−/− (KO, black bar) brain leukocytes were analyzed by flow cytometry, and total cellularity, numbers of blood derived infiltrating cells, and CD45Low microglial cells were compared. a–c After TBI, a significant increase in the overall cellularity was observed when comparing all groups at 15 days (*P < 0.05 comparing sham WT versus WT-TBI 15 days post-TBI), and these changes were sustained 30 days post-TBI. CD45High hematogenous population did not show statistical significance among injured WT and KO mice. d–f There was a significant increase in microglial cell number at 15 days post-TBI in WT mice when compared to sham WT group. CX3CR1 KO-TBI group also showed a significant increase in microglia number when comparing 15 and 30 days post-TBI, although effects were also seen in the sham-treated KO group. g–i Staining for Ki67 in representative sample of WT-TBI (g upper panel) and KO-TBI (g lower panel) groups and also presented in histogram (h) with gray line showing the isotype controls, WT-TBI Ki67 intensity in blue line, and KO-TBI in red. Data were quantified (i) revealing that in the absence of CX3CR1, microglial cells exhibit a higher proliferative capacity (*P < 0.05)
Fig. 4 Increased microglial reaction after TBI. CX3CR1+/+ (WT; white bar) and CX3CR1−/− (KO, black bar) brain leukocytes were analyzed by flow cytometry, and total cellularity, numbers of blood derived infiltrating cells, and CD45Low microglial cells were compared. a–c After TBI, a significant increase in the overall cellularity was observed when comparing all groups at 15 days (*P < 0.05 comparing sham WT versus WT-TBI 15 days post-TBI), and these changes were sustained 30 days post-TBI. CD45High hematogenous population did not show statistical significance among injured WT and KO mice. d–f There was a significant increase in microglial cell number at 15 days post-TBI in WT mice when compared to sham WT group. CX3CR1 KO-TBI group also showed a significant increase in microglia number when comparing 15 and 30 days post-TBI, although effects were also seen in the sham-treated KO group. g–i Staining for Ki67 in representative sample of WT-TBI (g upper panel) and KO-TBI (g lower panel) groups and also presented in histogram (h) with gray line showing the isotype controls, WT-TBI Ki67 intensity in blue line, and KO-TBI in red. Data were quantified (i) revealing that in the absence of CX3CR1, microglial cells exhibit a higher proliferative capacity (*P < 0.05)CC BY · PubMed Central
Fig. 5 Stereological quantification of CD11B+ cells in the cortex at 15 and 30 days post-injury. a ×10 magnification micrographs of CD11B staining in the cortex in the vicinity of the lesion. Upper panel shows the staining’s intensity in CX3CR1 sham WT and CX3CR1 WT-TBI at 15 and 30 days post-injury. Lower panels show the staining’s intensity in CX3CR1 sham KO and CX3CR1 KO-TBI at 15 and 30 days post-injury. b The cortical expression of CD11b+ cells was significantly increased in CX3CR1 KO-TBI (n = 6) mice compared to CX3CR1 WT-TBI mice (n = 5) at 15 days post-TBI (*p = 0.05). Two-way ANOVA revealed that the number of CD11b+ cells increased in the cortex from day 15–30 post-TBI to the same extent in CX3CR1 WT-TBI and in CX3CR1 KO-TBI mice (±± p = 0.001). Staining in sham animals was not determined (nd). CX3CR1 sham WT (white bar), CX3CR1 sham KO (green bar), CX3CR1 WT-TBI (red bar), CX3CR1 KO-TBI (blue bar)
Fig. 5 Stereological quantification of CD11B+ cells in the cortex at 15 and 30 days post-injury. a ×10 magnification micrographs of CD11B staining in the cortex in the vicinity of the lesion. Upper panel shows the staining’s intensity in CX3CR1 sham WT and CX3CR1 WT-TBI at 15 and 30 days post-injury. Lower panels show the staining’s intensity in CX3CR1 sham KO and CX3CR1 KO-TBI at 15 and 30 days post-injury. b The cortical expression of CD11b+ cells was significantly increased in CX3CR1 KO-TBI (n = 6) mice compared to CX3CR1 WT-TBI mice (n = 5) at 15 days post-TBI (*p = 0.05). Two-way ANOVA revealed that the number of CD11b+ cells increased in the cortex from day 15–30 post-TBI to the same extent in CX3CR1 WT-TBI and in CX3CR1 KO-TBI mice (±± p = 0.001). Staining in sham animals was not determined (nd). CX3CR1 sham WT (white bar), CX3CR1 sham KO (green bar), CX3CR1 WT-TBI (red bar), CX3CR1 KO-TBI (blue bar)CC BY · PubMed Central
Fig. 6 Immunostaining, stereological quantification, and qPCR analysis of M2 and M1 polarization markers in cortex at 7 days post-TBI. a–d YM1 shows a strong increase in staining in the CX3CR1 KO-TBI compared to CX3CR1 WT-TBI at 7 days post-injury. a Micrograph at ×4 magnification showing YM1 staining in the proximity of the lesion area in CX3CR1 KO-TBI mice. b Higher magnification (×10) of the area indicated by the red arrow in (a). c Higher magnification (×20) of the area in the proximity of the lesion of CX3CR1 WT-TBI and CX3CR1 KO-TBI showing in more detail microglial YM1 morphology. d Unbiased stereology revealed a significant increase in the number of YM1 and CD2O6+ cells (right panel) in the cortex of CX3CR1 KO-TBI mice (n = 3) compared to CX3CR1 WT-TBI (n = 4). e–h CD206 shows a strong increase in staining in the CX3CR1 KO-TBI compared to CX3CR1 WT-TBI at 7 days post-injury. e Micrograph at ×4 magnification showing CD206 staining in the proximity of the lesion area in CX3CR1 KO-TBI mice. f Higher magnification (×10) of the area indicated by the red arrow in (a). g Higher magnification (×20) of the area in the proximity of the lesion of CX3CR1 WT-TBI and CX3CR1 KO-TBI showing in more detail microglial CD206 morphology. h Unbiased stereology revealed a significant increase in the number of CD2O6+ cells in the cortex of CX3CR1 KO-TBI mice compared to CX3CR1 WT-TBI. YM1 and CD206 were not detected in sham mice (**p < 0.001). i Relative mRNA levels of M2 marker TGFβ were significantly lower in sham CX3CR1 sham KO (n = 5) compared to CX3CR1 sham WT (n = 5). Following TBI, the expression of TGFβ significantly increased in CX3CR1 KO mice compared to sham (n = 5; **p < 0.001) but was not different compared to CX3CR1 WT-TBI (n = 5). M1 markers iNOS (middle panel) and IL-1β (right panel) were similar in the cortex of CX3CR1 sham KO (n = 5) compared to CX3CR1 sham WT (n = 5). Following injury, iNOS and IL-1β mRNA levels in CX3CR1 KO-TBI (n = 5) were significantly decreased compared to CX3CR1 WT-TBI (n = 5). **p < 0.001). CX3CR1 sham WT (white bar), CX3CR1 sham KO (green bar), CX3CR1 WT-TBI (red bar), and CX3CR1 KO-TBI (blue bar)
Fig. 6 Immunostaining, stereological quantification, and qPCR analysis of M2 and M1 polarization markers in cortex at 7 days post-TBI. a–d YM1 shows a strong increase in staining in the CX3CR1 KO-TBI compared to CX3CR1 WT-TBI at 7 days post-injury. a Micrograph at ×4 magnification showing YM1 staining in the proximity of the lesion area in CX3CR1 KO-TBI mice. b Higher magnification (×10) of the area indicated by the red arrow in (a). c Higher magnification (×20) of the area in the proximity of the lesion of CX3CR1 WT-TBI and CX3CR1 KO-TBI showing in more detail microglial YM1 morphology. d Unbiased stereology revealed a significant increase in the number of YM1 and CD2O6+ cells (right panel) in the cortex of CX3CR1 KO-TBI mice (n = 3) compared to CX3CR1 WT-TBI (n = 4). e–h CD206 shows a strong increase in staining in the CX3CR1 KO-TBI compared to CX3CR1 WT-TBI at 7 days post-injury. e Micrograph at ×4 magnification showing CD206 staining in the proximity of the lesion area in CX3CR1 KO-TBI mice. f Higher magnification (×10) of the area indicated by the red arrow in (a). g Higher magnification (×20) of the area in the proximity of the lesion of CX3CR1 WT-TBI and CX3CR1 KO-TBI showing in more detail microglial CD206 morphology. h Unbiased stereology revealed a significant increase in the number of CD2O6+ cells in the cortex of CX3CR1 KO-TBI mice compared to CX3CR1 WT-TBI. YM1 and CD206 were not detected in sham mice (**p < 0.001). i Relative mRNA levels of M2 marker TGFβ were significantly lower in sham CX3CR1 sham KO (n = 5) compared to CX3CR1 sham WT (n = 5). Following TBI, the expression of TGFβ significantly increased in CX3CR1 KO mice compared to sham (n = 5; **p < 0.001) but was not different compared to CX3CR1 WT-TBI (n = 5). M1 markers iNOS (middle panel) and IL-1β (right panel) were similar in the cortex of CX3CR1 sham KO (n = 5) compared to CX3CR1 sham WT (n = 5). Following injury, iNOS and IL-1β mRNA levels in CX3CR1 KO-TBI (n = 5) were significantly decreased compared to CX3CR1 WT-TBI (n = 5). **p < 0.001). CX3CR1 sham WT (white bar), CX3CR1 sham KO (green bar), CX3CR1 WT-TBI (red bar), and CX3CR1 KO-TBI (blue bar)CC BY · PubMed Central
Fig. 7 a–c Fifteen days post-injury, CX3CR1 WT mice show increased protein levels of IL-1 (a), IL-6 (b), and decreased levels of IL-4 (c). CX3CR1 KO-TBI mice show increased IL-4 protein levels. CX3CR1 sham WT (white bar), CX3CR1 sham KO (green bar), CX3CR1 WT-TBI (red bar), and CX3CR1 KO-TBI (blue bar) (*P < 0.05)
Fig. 7 a–c Fifteen days post-injury, CX3CR1 WT mice show increased protein levels of IL-1 (a), IL-6 (b), and decreased levels of IL-4 (c). CX3CR1 KO-TBI mice show increased IL-4 protein levels. CX3CR1 sham WT (white bar), CX3CR1 sham KO (green bar), CX3CR1 WT-TBI (red bar), and CX3CR1 KO-TBI (blue bar) (*P < 0.05)CC BY · PubMed Central
Fig. 8 Immunostaining and stereological quantification for M1 polarization markers in hippocampus at 30 days post-TBI. a Micrograph at ×4 magnification showing Marco staining at 30 days post-TBI in the dentate gyrus of CX3CR1 WT-TBI and CX3CR1 KO-TBI mice. b Higher magnification (×20) of the dentate gyrus of CX3CR1 WT-TBI and CX3CR1 KO-TBI showing in the hippocampus show a strong increase in staining in the CX3CR1 KO-TBI compared to CX3CR1 WT-TBI at 30 days. c Unbiased stereology quantification of Marco revealed a significant increase in the number of Marco+ cells in the hippocampus of CX3CR1 KO-TBI compared to CX3CR1 WT-TBI (p < 0.001). d Micrograph at ×20 magnification of the dentate gyrus of CX3CR1 WT-TBI and CX3CR1 KO-TBI showing in the hippocampus show a strong increase in CD68 staining in the CX3CR1 KO-TBI compared to CX3CR1 WT-TBI at 30 days post-TBI. e Time course of CD68 expression at 15 and 30 days post-injury. Stereological quantification of CD68+ cells revealed a significant decrease in CX3CR1 KO-TBI mice compared to CX3CR1 WT-TBI at 15 days post-TBI. Although the difference did not reach statistical significance, at 30 days post-TBI, expression of CD68 was higher in CX3CR1 KO-TBI mice compared to wild-type (**p < 0.001)
Fig. 8 Immunostaining and stereological quantification for M1 polarization markers in hippocampus at 30 days post-TBI. a Micrograph at ×4 magnification showing Marco staining at 30 days post-TBI in the dentate gyrus of CX3CR1 WT-TBI and CX3CR1 KO-TBI mice. b Higher magnification (×20) of the dentate gyrus of CX3CR1 WT-TBI and CX3CR1 KO-TBI showing in the hippocampus show a strong increase in staining in the CX3CR1 KO-TBI compared to CX3CR1 WT-TBI at 30 days. c Unbiased stereology quantification of Marco revealed a significant increase in the number of Marco+ cells in the hippocampus of CX3CR1 KO-TBI compared to CX3CR1 WT-TBI (p < 0.001). d Micrograph at ×20 magnification of the dentate gyrus of CX3CR1 WT-TBI and CX3CR1 KO-TBI showing in the hippocampus show a strong increase in CD68 staining in the CX3CR1 KO-TBI compared to CX3CR1 WT-TBI at 30 days post-TBI. e Time course of CD68 expression at 15 and 30 days post-injury. Stereological quantification of CD68+ cells revealed a significant decrease in CX3CR1 KO-TBI mice compared to CX3CR1 WT-TBI at 15 days post-TBI. Although the difference did not reach statistical significance, at 30 days post-TBI, expression of CD68 was higher in CX3CR1 KO-TBI mice compared to wild-type (**p < 0.001)CC BY · PubMed Central

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Research works printed but not linked: 2

  1. Frank-Cannon TC, Alto LT, McAlpine FE, Tansey MG. Does neuroinflammation fan the flame in neurodegenerative diseases? Mol Neurodegener. 2009;4:47. · DOI · Paper page
  2. Gaetani P, Pisano P, Solinas G, Colombo P, Destro A, Levi D, et al. Immunohistohemical expression of the chemokine fractalkine and its receptor in the human brain cortex after severe traumatic brain injury and brain hemorrhage. J Neurosurg Sci. 2013;57(1):55–62.

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Metadata

Authors
Febinger, H. Y., Thomasy, H. E., Pavlova, M. N., Ringgold, K. M., Barf, P. R., George, A. M., Grillo, J. N., Bachstetter, A. D., Garcia, J. A., Cardona, A. E., Opp, M. R., & Gemma, C.
Affiliations
  • University of Washington (US)
  • University of Kentucky (US)
  • The University of Texas at San Antonio (US)
Corresponding author
Gemma, Carmelina
ORCID
Venue
Journal of Neuroinflammation
Publisher
Springer Science and Business Media LLC
Published
2015-09-02
Volume
12
Issue
1
Pages
154-154
ISSN
1742-2094 (ISSN-L)
DOI
10.1186/s12974-015-0386-5
PMC
PMC4557842
OpenAlex
W1944546979
Cited by
110
References
58
Citations by year
2026: 10 · 2025: 8 · 2024: 5 · 2023: 10 · 2022: 6 · 2021: 15 · 2020: 10 · 2019: 13 · 2018: 16 · 2017: 7 · 2016: 9 · 2015: 1
FWCI
7.76
Type
journal article
Language
en
Open access
Licence
Locations
  • Journal of Neuroinflammation (publishedVersion, cc-by)
  • Europe PMC (PubMed Central) (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • UKnowledge (University of Kentucky) (submittedVersion, cc-by)
Funders
National Institutes of Health (SC1GM095426)
Topics
  • Health Sciences › Medicine › Clinical Neurology › Traumatic Brain Injury and Neurovascular Disturbances
  • Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
  • Health Sciences › Medicine › Clinical Neurology › Traumatic Brain Injury Research
Keywords
CX3CR1, fractalkine, mild traumatic brain injury, microglial activation, M1/M2 microglial polarization, neuroinflammation, controlled cortical impact, neuronal cell death, cognitive impairment, CX3CR1 knockout mice
MeSH terms
CX3C Chemokine Receptor 1, Analysis of Variance, Animals, Brain, Brain Injuries, Disease Models, Animal, Exploratory Behavior, Flow Cytometry, Fluoresceins, Leukocytes, Mononuclear, Macrophage Activation, Male, Mice, Transgenic, Neurons, Psychomotor Disorders, Time Factors, Maze Learning, Receptors, Chemokine, Rotarod Performance Test, Green Fluorescent Proteins, Mice

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

What counts as a claim ›How we measure confidence ›How we check this ›

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