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Age exacerbates the CCR2/5-mediated neuroinflammatory response to traumatic brain injury.

Morganti JM, Riparip LK, Chou A, Liu S, Gupta N, Rosi S - J Neuroinflammation (2016)

Bottom Line: The recruitment of peripheral CCR2(+) macrophages was delineated using the CX3CR1 (GFP/+) CCR2 (RFP/+) reporter mouse.Using a unique reporter animal model able to discriminate resident versus peripherally derived myeloid cells, we demonstrate that in the aged brain, there is an increased accumulation of peripherally derived CCR2(+) macrophages after TBI compared to young animals.Targeting this cellular response with cenicriviroc, a dual CCR2/5 antagonist, significantly ameliorated injury-induced sequelae in the aged TBI animals.

View Article: PubMed Central - PubMed

Affiliation: Brain and Spinal Injury Center, University of California, 1001 Potrero Ave, Bldg. 1, Room 101, San Francisco, CA, 94110, USA.

ABSTRACT

Background: Traumatic brain injury (TBI) is a major risk factor for the development of multiple neurodegenerative diseases, including Alzheimer's disease (AD) and numerous recent reports document the development of dementia after TBI. Age is a significant factor in both the risk of and the incidence of acquired brain injury. TBI-induced inflammatory response is associated with activation of brain resident microglia and accumulation of infiltrating monocytes, which plays a pivotal role in chronic neurodegeneration and loss of neurological function after TBI. Despite the extensive clinical evidence implicating neuroinflammation with the TBI-related sequelae, the specific role of these different myeloid cells and the influence of age on TBI-initiated innate immune response remain unknown and poorly studied.

Methods: We used gene profiling and pathway analysis to define the effect of age on inflammatory response at the time of injury. The recruitment of peripheral CCR2(+) macrophages was delineated using the CX3CR1 (GFP/+) CCR2 (RFP/+) reporter mouse. These responses were examined in the context of CCR2/5 antagonism using cenicriviroc.

Results: Unsupervised gene clustering and pathway analysis revealed that age predisposes exacerbated inflammatory response related to the recruitment and activation of peripheral monocytes to the injured brain. Using a unique reporter animal model able to discriminate resident versus peripherally derived myeloid cells, we demonstrate that in the aged brain, there is an increased accumulation of peripherally derived CCR2(+) macrophages after TBI compared to young animals. Exaggerated recruitment of this population of cells was associated with an augmented inflammatory response in the aged TBI animals. Targeting this cellular response with cenicriviroc, a dual CCR2/5 antagonist, significantly ameliorated injury-induced sequelae in the aged TBI animals.

Conclusions: Importantly, these findings demonstrate that peripheral monocytes play a non-redundant and contributing role to the etiology of trauma-induced inflammatory sequelae in the aged brain.

No MeSH data available.


Related in: MedlinePlus

Age exacerbates inflammatory gene signatures after TBI. Overall, the aged TBI group had exacerbated responses, whether up- or downregulated, to TBI when compared to their young TBI counterparts. Select genes from each of the three clusters were validated using n = 8/group. a Genes from the “green” hierarchical cluster aligned with pooled responses observed in the array. Specifically, detailing that age significantly affected, via downregulation, gene expression of CD163, CX3CL1, and JAK2, but not JMJD3, which had only a visual trend. b Genes selected from the “red” cluster for analysis showed marked upregulation of CD86, CCL5, CCL8, and CCL7 in the aged TBI group. c Similarly, genes from the “aquamarine” hierarchical cluster all displayed significant upregulation in expression response as a function of age, compared to young TBI. YT young TBI; magenta, AS aged sham; aquamarine, AT aged TBI; orange. Young sham expression values are equivalent to zero. Data were analyzed using two-way ANOVA with Tukey’s PSD for multiple comparisons and presented as mean + SEM. *p < 0.05, **p < 0.01 comparing young TBI to young sham. #p < 0.05, ##p < 0.01 comparing aged TBI to young TBI
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Fig2: Age exacerbates inflammatory gene signatures after TBI. Overall, the aged TBI group had exacerbated responses, whether up- or downregulated, to TBI when compared to their young TBI counterparts. Select genes from each of the three clusters were validated using n = 8/group. a Genes from the “green” hierarchical cluster aligned with pooled responses observed in the array. Specifically, detailing that age significantly affected, via downregulation, gene expression of CD163, CX3CL1, and JAK2, but not JMJD3, which had only a visual trend. b Genes selected from the “red” cluster for analysis showed marked upregulation of CD86, CCL5, CCL8, and CCL7 in the aged TBI group. c Similarly, genes from the “aquamarine” hierarchical cluster all displayed significant upregulation in expression response as a function of age, compared to young TBI. YT young TBI; magenta, AS aged sham; aquamarine, AT aged TBI; orange. Young sham expression values are equivalent to zero. Data were analyzed using two-way ANOVA with Tukey’s PSD for multiple comparisons and presented as mean + SEM. *p < 0.05, **p < 0.01 comparing young TBI to young sham. #p < 0.05, ##p < 0.01 comparing aged TBI to young TBI

Mentions: Selected genes were validated within each of the green, red, and aquamarine clusters of interest. In line with the pooled observations from the array and cluster, four genes from the green cluster (Fig. 1): CD163, CX3CL1, JAK2, and JMJD3 were disproportionately downregulated in the aged TBI group, compared to young TBI (Fig. 2a). Potentially indicating that as a result of age, there is a maladaptive response to injury related to the restraint of macrophage activation, similar to what is observed in humans [16]. Interestingly, we show that the anti-inflammatory [17] chemokine CX3CL1 is significantly downregulated in the aged TBI group compared to young animals following TBI. These findings are similar to a report on brain aging in healthy rodents that showed CX3CL1 expression is decreased with age [18], which can lead to pro-inflammatory neurotoxic responses [19, 20].Fig. 2


Age exacerbates the CCR2/5-mediated neuroinflammatory response to traumatic brain injury.

Morganti JM, Riparip LK, Chou A, Liu S, Gupta N, Rosi S - J Neuroinflammation (2016)

Age exacerbates inflammatory gene signatures after TBI. Overall, the aged TBI group had exacerbated responses, whether up- or downregulated, to TBI when compared to their young TBI counterparts. Select genes from each of the three clusters were validated using n = 8/group. a Genes from the “green” hierarchical cluster aligned with pooled responses observed in the array. Specifically, detailing that age significantly affected, via downregulation, gene expression of CD163, CX3CL1, and JAK2, but not JMJD3, which had only a visual trend. b Genes selected from the “red” cluster for analysis showed marked upregulation of CD86, CCL5, CCL8, and CCL7 in the aged TBI group. c Similarly, genes from the “aquamarine” hierarchical cluster all displayed significant upregulation in expression response as a function of age, compared to young TBI. YT young TBI; magenta, AS aged sham; aquamarine, AT aged TBI; orange. Young sham expression values are equivalent to zero. Data were analyzed using two-way ANOVA with Tukey’s PSD for multiple comparisons and presented as mean + SEM. *p < 0.05, **p < 0.01 comparing young TBI to young sham. #p < 0.05, ##p < 0.01 comparing aged TBI to young TBI
© Copyright Policy - OpenAccess
Related In: Results  -  Collection

License 1 - License 2
Show All Figures
getmorefigures.php?uid=PMC4835854&req=5

Fig2: Age exacerbates inflammatory gene signatures after TBI. Overall, the aged TBI group had exacerbated responses, whether up- or downregulated, to TBI when compared to their young TBI counterparts. Select genes from each of the three clusters were validated using n = 8/group. a Genes from the “green” hierarchical cluster aligned with pooled responses observed in the array. Specifically, detailing that age significantly affected, via downregulation, gene expression of CD163, CX3CL1, and JAK2, but not JMJD3, which had only a visual trend. b Genes selected from the “red” cluster for analysis showed marked upregulation of CD86, CCL5, CCL8, and CCL7 in the aged TBI group. c Similarly, genes from the “aquamarine” hierarchical cluster all displayed significant upregulation in expression response as a function of age, compared to young TBI. YT young TBI; magenta, AS aged sham; aquamarine, AT aged TBI; orange. Young sham expression values are equivalent to zero. Data were analyzed using two-way ANOVA with Tukey’s PSD for multiple comparisons and presented as mean + SEM. *p < 0.05, **p < 0.01 comparing young TBI to young sham. #p < 0.05, ##p < 0.01 comparing aged TBI to young TBI
Mentions: Selected genes were validated within each of the green, red, and aquamarine clusters of interest. In line with the pooled observations from the array and cluster, four genes from the green cluster (Fig. 1): CD163, CX3CL1, JAK2, and JMJD3 were disproportionately downregulated in the aged TBI group, compared to young TBI (Fig. 2a). Potentially indicating that as a result of age, there is a maladaptive response to injury related to the restraint of macrophage activation, similar to what is observed in humans [16]. Interestingly, we show that the anti-inflammatory [17] chemokine CX3CL1 is significantly downregulated in the aged TBI group compared to young animals following TBI. These findings are similar to a report on brain aging in healthy rodents that showed CX3CL1 expression is decreased with age [18], which can lead to pro-inflammatory neurotoxic responses [19, 20].Fig. 2

Bottom Line: The recruitment of peripheral CCR2(+) macrophages was delineated using the CX3CR1 (GFP/+) CCR2 (RFP/+) reporter mouse.Using a unique reporter animal model able to discriminate resident versus peripherally derived myeloid cells, we demonstrate that in the aged brain, there is an increased accumulation of peripherally derived CCR2(+) macrophages after TBI compared to young animals.Targeting this cellular response with cenicriviroc, a dual CCR2/5 antagonist, significantly ameliorated injury-induced sequelae in the aged TBI animals.

View Article: PubMed Central - PubMed

Affiliation: Brain and Spinal Injury Center, University of California, 1001 Potrero Ave, Bldg. 1, Room 101, San Francisco, CA, 94110, USA.

ABSTRACT

Background: Traumatic brain injury (TBI) is a major risk factor for the development of multiple neurodegenerative diseases, including Alzheimer's disease (AD) and numerous recent reports document the development of dementia after TBI. Age is a significant factor in both the risk of and the incidence of acquired brain injury. TBI-induced inflammatory response is associated with activation of brain resident microglia and accumulation of infiltrating monocytes, which plays a pivotal role in chronic neurodegeneration and loss of neurological function after TBI. Despite the extensive clinical evidence implicating neuroinflammation with the TBI-related sequelae, the specific role of these different myeloid cells and the influence of age on TBI-initiated innate immune response remain unknown and poorly studied.

Methods: We used gene profiling and pathway analysis to define the effect of age on inflammatory response at the time of injury. The recruitment of peripheral CCR2(+) macrophages was delineated using the CX3CR1 (GFP/+) CCR2 (RFP/+) reporter mouse. These responses were examined in the context of CCR2/5 antagonism using cenicriviroc.

Results: Unsupervised gene clustering and pathway analysis revealed that age predisposes exacerbated inflammatory response related to the recruitment and activation of peripheral monocytes to the injured brain. Using a unique reporter animal model able to discriminate resident versus peripherally derived myeloid cells, we demonstrate that in the aged brain, there is an increased accumulation of peripherally derived CCR2(+) macrophages after TBI compared to young animals. Exaggerated recruitment of this population of cells was associated with an augmented inflammatory response in the aged TBI animals. Targeting this cellular response with cenicriviroc, a dual CCR2/5 antagonist, significantly ameliorated injury-induced sequelae in the aged TBI animals.

Conclusions: Importantly, these findings demonstrate that peripheral monocytes play a non-redundant and contributing role to the etiology of trauma-induced inflammatory sequelae in the aged brain.

No MeSH data available.


Related in: MedlinePlus