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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

Inflammatory profiling of the TBI brain. Ipsilateral hippocampi pooled from sham and injured animals (n = 8/group) of 3-month (young; Y) and 23-month (aged; A) 24 h after surgery for gene array analysis. Inflammatory profiling array revealed clusters of enrichment and downregulation of genes across three groups; young TBI, aged sham, and aged TBI, relative to young sham expression levels, all data were Log2 transformed. Three specific clusters were examined, wherein the genes within the green cluster were downregulated in the aged TBI group, the red gene cluster showed marked enrichment for aged TBI, and lastly the aquamarine cluster showed similar enrichment of genes as a response to TBI, regardless of age. In heatmap; teal downregulated, red upregulated
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Fig1: Inflammatory profiling of the TBI brain. Ipsilateral hippocampi pooled from sham and injured animals (n = 8/group) of 3-month (young; Y) and 23-month (aged; A) 24 h after surgery for gene array analysis. Inflammatory profiling array revealed clusters of enrichment and downregulation of genes across three groups; young TBI, aged sham, and aged TBI, relative to young sham expression levels, all data were Log2 transformed. Three specific clusters were examined, wherein the genes within the green cluster were downregulated in the aged TBI group, the red gene cluster showed marked enrichment for aged TBI, and lastly the aquamarine cluster showed similar enrichment of genes as a response to TBI, regardless of age. In heatmap; teal downregulated, red upregulated

Mentions: We first conducted gene profiling of the injured parenchyma to examine the effect of age upon neuroinflammatory response to injury. Unsupervised hierarchical clustering (Fig. 1) revealed unique arrangements of both enriched and downregulated responses as a result of injury and/or age. Of these expression clusters, we examined three that visually represented alignment of genes that were downregulated in the aged TBI group (Fig. 1; green), upregulated in the aged TBI group (Fig. 1; red), and upregulated as a result of injury (Fig. 1; aquamarine). In general, the downregulated genes of the green cluster represented a repressed inflammatory function as a combination of age and injury. By contrast, the red cluster linked a group of genes related to recruitment and activation of pro-inflammatory monocytes. Notably, within this expression cluster, our data show increased responses of several CCR2 and CCR5 cognate ligands (e.g., CCL2, CCL7, CCL8, CCL5). While the aquamarine (Fig. 1) cluster was distinct from the changes found within the red cluster, there was a similar activation profile found between both TBI groups hierarchically. There was a heterogeneous mix of chemokines, cytokines, and signal transducers, and metabolic mediators found throughout this gene cluster, which seem to be indicative of a general inflammatory response to brain injury, as there was little to no activation of these mediators in the aged sham group (Fig. 1).Fig. 1


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)

Inflammatory profiling of the TBI brain. Ipsilateral hippocampi pooled from sham and injured animals (n = 8/group) of 3-month (young; Y) and 23-month (aged; A) 24 h after surgery for gene array analysis. Inflammatory profiling array revealed clusters of enrichment and downregulation of genes across three groups; young TBI, aged sham, and aged TBI, relative to young sham expression levels, all data were Log2 transformed. Three specific clusters were examined, wherein the genes within the green cluster were downregulated in the aged TBI group, the red gene cluster showed marked enrichment for aged TBI, and lastly the aquamarine cluster showed similar enrichment of genes as a response to TBI, regardless of age. In heatmap; teal downregulated, red upregulated
© Copyright Policy - OpenAccess
Related In: Results  -  Collection

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

Fig1: Inflammatory profiling of the TBI brain. Ipsilateral hippocampi pooled from sham and injured animals (n = 8/group) of 3-month (young; Y) and 23-month (aged; A) 24 h after surgery for gene array analysis. Inflammatory profiling array revealed clusters of enrichment and downregulation of genes across three groups; young TBI, aged sham, and aged TBI, relative to young sham expression levels, all data were Log2 transformed. Three specific clusters were examined, wherein the genes within the green cluster were downregulated in the aged TBI group, the red gene cluster showed marked enrichment for aged TBI, and lastly the aquamarine cluster showed similar enrichment of genes as a response to TBI, regardless of age. In heatmap; teal downregulated, red upregulated
Mentions: We first conducted gene profiling of the injured parenchyma to examine the effect of age upon neuroinflammatory response to injury. Unsupervised hierarchical clustering (Fig. 1) revealed unique arrangements of both enriched and downregulated responses as a result of injury and/or age. Of these expression clusters, we examined three that visually represented alignment of genes that were downregulated in the aged TBI group (Fig. 1; green), upregulated in the aged TBI group (Fig. 1; red), and upregulated as a result of injury (Fig. 1; aquamarine). In general, the downregulated genes of the green cluster represented a repressed inflammatory function as a combination of age and injury. By contrast, the red cluster linked a group of genes related to recruitment and activation of pro-inflammatory monocytes. Notably, within this expression cluster, our data show increased responses of several CCR2 and CCR5 cognate ligands (e.g., CCL2, CCL7, CCL8, CCL5). While the aquamarine (Fig. 1) cluster was distinct from the changes found within the red cluster, there was a similar activation profile found between both TBI groups hierarchically. There was a heterogeneous mix of chemokines, cytokines, and signal transducers, and metabolic mediators found throughout this gene cluster, which seem to be indicative of a general inflammatory response to brain injury, as there was little to no activation of these mediators in the aged sham group (Fig. 1).Fig. 1

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