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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

Gene profiling predicts exaggerated activation and recruitment of monocytes in aged TBI. Gene array data were uploaded into IPA software, genes with a fold change (relative to young sham) ≥1.5 or ≤−1.5 were included for disease and biological function analysis. a Upregulated functions across all three groups were sorted by activation z-score of the aged TBI group, only the top ten functions are presented with the black arrow emphasizing the activation of monocytes. b Functional network diagram of predicted and measured regulators is presented for both young TBI and aged TBI, which highlight an overrepresented activation for this function for aged TBI group. c Using Dbl-Het reporter mice (n = 6/group), macrophages (CD11b+F4/80+) were delineated based upon their relative expression of GFP (CX3CR1) from RFP (CCR2) by flow cytometry. There were relatively very few CCR2+ macrophages (blue box) in the sham animals; however, there was a significant increase in this subpopulation due to age. However, 24 h following TBI, there was a significant increase in the mean number of CCR2+ macrophages (blue box) in the aged animals compared to young. Data were analyzed using Student’s t test and are represented by the mean + SEM. **p < 0.01
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Fig4: Gene profiling predicts exaggerated activation and recruitment of monocytes in aged TBI. Gene array data were uploaded into IPA software, genes with a fold change (relative to young sham) ≥1.5 or ≤−1.5 were included for disease and biological function analysis. a Upregulated functions across all three groups were sorted by activation z-score of the aged TBI group, only the top ten functions are presented with the black arrow emphasizing the activation of monocytes. b Functional network diagram of predicted and measured regulators is presented for both young TBI and aged TBI, which highlight an overrepresented activation for this function for aged TBI group. c Using Dbl-Het reporter mice (n = 6/group), macrophages (CD11b+F4/80+) were delineated based upon their relative expression of GFP (CX3CR1) from RFP (CCR2) by flow cytometry. There were relatively very few CCR2+ macrophages (blue box) in the sham animals; however, there was a significant increase in this subpopulation due to age. However, 24 h following TBI, there was a significant increase in the mean number of CCR2+ macrophages (blue box) in the aged animals compared to young. Data were analyzed using Student’s t test and are represented by the mean + SEM. **p < 0.01

Mentions: Comparatively, we examined if these gene expression responses were predictive of downstream disease-based functions using IPA software. Using IPA comparative analysis, we next sorted the top ten biological functions by the activation z-score in the aged TBI group. Of the top ten functions generated, there was a general theme of each related to innate immune response. In particular, there was an overrepresentation with both the differentiation and activation of monocytes in the aged TBI group, relative to young TBI (Fig. 4a; arrow). Examination of the putative response network associated with the activation of monocytes (Fig. 4a) revealed significant differential expression patterns in the mediators affecting this response system (Fig. 4b). Principal to this response was the induction of pro-inflammatory and chemotactic mediators within the CC and CXC motifs.Fig. 4


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)

Gene profiling predicts exaggerated activation and recruitment of monocytes in aged TBI. Gene array data were uploaded into IPA software, genes with a fold change (relative to young sham) ≥1.5 or ≤−1.5 were included for disease and biological function analysis. a Upregulated functions across all three groups were sorted by activation z-score of the aged TBI group, only the top ten functions are presented with the black arrow emphasizing the activation of monocytes. b Functional network diagram of predicted and measured regulators is presented for both young TBI and aged TBI, which highlight an overrepresented activation for this function for aged TBI group. c Using Dbl-Het reporter mice (n = 6/group), macrophages (CD11b+F4/80+) were delineated based upon their relative expression of GFP (CX3CR1) from RFP (CCR2) by flow cytometry. There were relatively very few CCR2+ macrophages (blue box) in the sham animals; however, there was a significant increase in this subpopulation due to age. However, 24 h following TBI, there was a significant increase in the mean number of CCR2+ macrophages (blue box) in the aged animals compared to young. Data were analyzed using Student’s t test and are represented by the mean + SEM. **p < 0.01
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Related In: Results  -  Collection

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Fig4: Gene profiling predicts exaggerated activation and recruitment of monocytes in aged TBI. Gene array data were uploaded into IPA software, genes with a fold change (relative to young sham) ≥1.5 or ≤−1.5 were included for disease and biological function analysis. a Upregulated functions across all three groups were sorted by activation z-score of the aged TBI group, only the top ten functions are presented with the black arrow emphasizing the activation of monocytes. b Functional network diagram of predicted and measured regulators is presented for both young TBI and aged TBI, which highlight an overrepresented activation for this function for aged TBI group. c Using Dbl-Het reporter mice (n = 6/group), macrophages (CD11b+F4/80+) were delineated based upon their relative expression of GFP (CX3CR1) from RFP (CCR2) by flow cytometry. There were relatively very few CCR2+ macrophages (blue box) in the sham animals; however, there was a significant increase in this subpopulation due to age. However, 24 h following TBI, there was a significant increase in the mean number of CCR2+ macrophages (blue box) in the aged animals compared to young. Data were analyzed using Student’s t test and are represented by the mean + SEM. **p < 0.01
Mentions: Comparatively, we examined if these gene expression responses were predictive of downstream disease-based functions using IPA software. Using IPA comparative analysis, we next sorted the top ten biological functions by the activation z-score in the aged TBI group. Of the top ten functions generated, there was a general theme of each related to innate immune response. In particular, there was an overrepresentation with both the differentiation and activation of monocytes in the aged TBI group, relative to young TBI (Fig. 4a; arrow). Examination of the putative response network associated with the activation of monocytes (Fig. 4a) revealed significant differential expression patterns in the mediators affecting this response system (Fig. 4b). Principal to this response was the induction of pro-inflammatory and chemotactic mediators within the CC and CXC motifs.Fig. 4

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