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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

IPA upstream analysis displays heterogeneous regulatory components associated with inflammatory response. Gene array data were loaded into IPA software; genes with a fold change (relative to young sham) ≥1.5 or ≤−1.5 were included for upstream regulator analysis. a Upregulated and downregulated molecules were sorted via their respective activation z-score and the top ten regulators (up and down) are presented for each condition. b, c Representative regulatory networks for putative upstream mediators associated with young TBI and aged TBI, with CCL2 representing an upregulated response and GPX1 representing a downregulated response. Both CCL2 and GPX1 show dissimilar expression responses for young TBI versus aged TBI
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Fig3: IPA upstream analysis displays heterogeneous regulatory components associated with inflammatory response. Gene array data were loaded into IPA software; genes with a fold change (relative to young sham) ≥1.5 or ≤−1.5 were included for upstream regulator analysis. a Upregulated and downregulated molecules were sorted via their respective activation z-score and the top ten regulators (up and down) are presented for each condition. b, c Representative regulatory networks for putative upstream mediators associated with young TBI and aged TBI, with CCL2 representing an upregulated response and GPX1 representing a downregulated response. Both CCL2 and GPX1 show dissimilar expression responses for young TBI versus aged TBI

Mentions: Next, we examined the gene expression profiles for translational observations through identification of putative upstream and downstream functional analyses using IPA software. This software converts gene expression data into recognized functional matrices related to disease etiology. Using this approach, IPA software identified regulatory genes associated with predicted upstream networks (Fig. 3a). Of these putative regulators, we sorted these responses by descending activation z-score and selected the top ten regulators that were either up- or downregulated for each of the three conditions (e.g., young TBI, aged sham, aged TBI), relative to young sham animals. These analyses revealed heterogeneous regulatory responses with respect to the variety of genes identified; however, there were a few instances where these regulators were conserved between conditions. Interestingly, among the conserved regulators between both young and aged TBI groups were the activation of CCL2 (Fig. 3b) and downregulation of GPX1 (Fig. 3c), involved in the recruitment of CCR2+ leukocytes and regulation of oxidative stress, respectively.Fig. 3


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)

IPA upstream analysis displays heterogeneous regulatory components associated with inflammatory response. Gene array data were loaded into IPA software; genes with a fold change (relative to young sham) ≥1.5 or ≤−1.5 were included for upstream regulator analysis. a Upregulated and downregulated molecules were sorted via their respective activation z-score and the top ten regulators (up and down) are presented for each condition. b, c Representative regulatory networks for putative upstream mediators associated with young TBI and aged TBI, with CCL2 representing an upregulated response and GPX1 representing a downregulated response. Both CCL2 and GPX1 show dissimilar expression responses for young TBI versus aged TBI
© Copyright Policy - OpenAccess
Related In: Results  -  Collection

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

Fig3: IPA upstream analysis displays heterogeneous regulatory components associated with inflammatory response. Gene array data were loaded into IPA software; genes with a fold change (relative to young sham) ≥1.5 or ≤−1.5 were included for upstream regulator analysis. a Upregulated and downregulated molecules were sorted via their respective activation z-score and the top ten regulators (up and down) are presented for each condition. b, c Representative regulatory networks for putative upstream mediators associated with young TBI and aged TBI, with CCL2 representing an upregulated response and GPX1 representing a downregulated response. Both CCL2 and GPX1 show dissimilar expression responses for young TBI versus aged TBI
Mentions: Next, we examined the gene expression profiles for translational observations through identification of putative upstream and downstream functional analyses using IPA software. This software converts gene expression data into recognized functional matrices related to disease etiology. Using this approach, IPA software identified regulatory genes associated with predicted upstream networks (Fig. 3a). Of these putative regulators, we sorted these responses by descending activation z-score and selected the top ten regulators that were either up- or downregulated for each of the three conditions (e.g., young TBI, aged sham, aged TBI), relative to young sham animals. These analyses revealed heterogeneous regulatory responses with respect to the variety of genes identified; however, there were a few instances where these regulators were conserved between conditions. Interestingly, among the conserved regulators between both young and aged TBI groups were the activation of CCL2 (Fig. 3b) and downregulation of GPX1 (Fig. 3c), involved in the recruitment of CCR2+ leukocytes and regulation of oxidative stress, respectively.Fig. 3

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