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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

Treatment with CVC attenuates age-related inflammatory and oxidative stress responses. a-c In a separate cohort (n = 8/group), inflammatory clusters were examined for their response to CVC treatment. a–c Correspond to the previously examined green, red, and aquamarine expression clusters, respectively. d Subunits of the NOX2 complex were measured as a response to CVC treatment (n = 8/group). Gene expression data are relative to vehicle-treated aged TBI. Vehicle expression values are equivalent to zero. Data were analyzed using Student’s t test are represented by mean + SEM. *p < 0.05, **p < 0.01, and ***p < 0.001
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Fig6: Treatment with CVC attenuates age-related inflammatory and oxidative stress responses. a-c In a separate cohort (n = 8/group), inflammatory clusters were examined for their response to CVC treatment. a–c Correspond to the previously examined green, red, and aquamarine expression clusters, respectively. d Subunits of the NOX2 complex were measured as a response to CVC treatment (n = 8/group). Gene expression data are relative to vehicle-treated aged TBI. Vehicle expression values are equivalent to zero. Data were analyzed using Student’s t test are represented by mean + SEM. *p < 0.05, **p < 0.01, and ***p < 0.001

Mentions: We next examined whether this treatment had any effect within the previously defined (Fig. 1) expression patterns identified by hierarchical clustering. Treatment with CVC significantly increased the expression of the genes in the green “restraint and anti-inflammatory” cluster (Fig. 6a), while significantly downregulating genes from the red “inflammatory chemotactic” cluster (Fig. 6b) and aquamarine “injury-induced inflammation” (Fig. 6c) gene clusters. The putative upstream network analysis predicted a proclivity for exaggerated oxidative stress response in the aged TBI group through downregulation of GPX1-regulated pathways (Fig. 3c). Importantly, we have recently shown that CCR2 antagonism ameliorates constituents mediating oxidative stress response following TBI through reduction of NADPH oxidase (NOX2) complex [13]. In agreement with those findings, our current data show that CVC treatment significantly downregulated multiple constituents of the neurotoxic ROS complex, NOX2 (Fig. 6d), which were previously shown to be upregulated in aged animals following TBI [22].Fig. 6


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)

Treatment with CVC attenuates age-related inflammatory and oxidative stress responses. a-c In a separate cohort (n = 8/group), inflammatory clusters were examined for their response to CVC treatment. a–c Correspond to the previously examined green, red, and aquamarine expression clusters, respectively. d Subunits of the NOX2 complex were measured as a response to CVC treatment (n = 8/group). Gene expression data are relative to vehicle-treated aged TBI. Vehicle expression values are equivalent to zero. Data were analyzed using Student’s t test are represented by mean + SEM. *p < 0.05, **p < 0.01, and ***p < 0.001
© Copyright Policy - OpenAccess
Related In: Results  -  Collection

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

Fig6: Treatment with CVC attenuates age-related inflammatory and oxidative stress responses. a-c In a separate cohort (n = 8/group), inflammatory clusters were examined for their response to CVC treatment. a–c Correspond to the previously examined green, red, and aquamarine expression clusters, respectively. d Subunits of the NOX2 complex were measured as a response to CVC treatment (n = 8/group). Gene expression data are relative to vehicle-treated aged TBI. Vehicle expression values are equivalent to zero. Data were analyzed using Student’s t test are represented by mean + SEM. *p < 0.05, **p < 0.01, and ***p < 0.001
Mentions: We next examined whether this treatment had any effect within the previously defined (Fig. 1) expression patterns identified by hierarchical clustering. Treatment with CVC significantly increased the expression of the genes in the green “restraint and anti-inflammatory” cluster (Fig. 6a), while significantly downregulating genes from the red “inflammatory chemotactic” cluster (Fig. 6b) and aquamarine “injury-induced inflammation” (Fig. 6c) gene clusters. The putative upstream network analysis predicted a proclivity for exaggerated oxidative stress response in the aged TBI group through downregulation of GPX1-regulated pathways (Fig. 3c). Importantly, we have recently shown that CCR2 antagonism ameliorates constituents mediating oxidative stress response following TBI through reduction of NADPH oxidase (NOX2) complex [13]. In agreement with those findings, our current data show that CVC treatment significantly downregulated multiple constituents of the neurotoxic ROS complex, NOX2 (Fig. 6d), which were previously shown to be upregulated in aged animals following TBI [22].Fig. 6

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