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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

Dual targeting of CCR2/5 with CVC mitigates TBI-induced macrophage recruitment. a In WT mice, CVC or vehicle was administered BID via oral gavage at 100 mg/kg at 2 and 10 h post surgery before animals were euthanized for various endpoints at 24 h following surgery. b A cohort of WT aged TBI animals (n = 8/group) was used for flow cytometry analysis of macrophage infiltration into the injured brain. Twenty-four hours after injury, there was a significant decrease in the number of peripheral macrophages (CD11b+F4/80+CD45hiLy6C+) in the CVC-treated animals compared to their vehicle-treated counterparts
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Fig5: Dual targeting of CCR2/5 with CVC mitigates TBI-induced macrophage recruitment. a In WT mice, CVC or vehicle was administered BID via oral gavage at 100 mg/kg at 2 and 10 h post surgery before animals were euthanized for various endpoints at 24 h following surgery. b A cohort of WT aged TBI animals (n = 8/group) was used for flow cytometry analysis of macrophage infiltration into the injured brain. Twenty-four hours after injury, there was a significant decrease in the number of peripheral macrophages (CD11b+F4/80+CD45hiLy6C+) in the CVC-treated animals compared to their vehicle-treated counterparts

Mentions: In order to abrogate this response, we treated aged TBI mice with cenicriviroc (CVC), a potent, oral, dual-antagonist of CCR2/5, which is currently being evaluated in a phase 2 clinical trial in adults with non-alcoholic fatty liver disease and liver fibrosis (NCT02217475). Separate cohorts of aged TBI animals were treated with either vehicle or CVC twice daily several hours after injury (Fig. 5a). Using this experimental approach, we observed a significant reduction in the numbers of CD11b+F4/80+CD45hiLy6C+ macrophages (Fig. 5b,c), which are analogous to CCR2+ macrophages, recruited into the diseased brain [12, 28].Fig. 5


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)

Dual targeting of CCR2/5 with CVC mitigates TBI-induced macrophage recruitment. a In WT mice, CVC or vehicle was administered BID via oral gavage at 100 mg/kg at 2 and 10 h post surgery before animals were euthanized for various endpoints at 24 h following surgery. b A cohort of WT aged TBI animals (n = 8/group) was used for flow cytometry analysis of macrophage infiltration into the injured brain. Twenty-four hours after injury, there was a significant decrease in the number of peripheral macrophages (CD11b+F4/80+CD45hiLy6C+) in the CVC-treated animals compared to their vehicle-treated counterparts
© Copyright Policy - OpenAccess
Related In: Results  -  Collection

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

Fig5: Dual targeting of CCR2/5 with CVC mitigates TBI-induced macrophage recruitment. a In WT mice, CVC or vehicle was administered BID via oral gavage at 100 mg/kg at 2 and 10 h post surgery before animals were euthanized for various endpoints at 24 h following surgery. b A cohort of WT aged TBI animals (n = 8/group) was used for flow cytometry analysis of macrophage infiltration into the injured brain. Twenty-four hours after injury, there was a significant decrease in the number of peripheral macrophages (CD11b+F4/80+CD45hiLy6C+) in the CVC-treated animals compared to their vehicle-treated counterparts
Mentions: In order to abrogate this response, we treated aged TBI mice with cenicriviroc (CVC), a potent, oral, dual-antagonist of CCR2/5, which is currently being evaluated in a phase 2 clinical trial in adults with non-alcoholic fatty liver disease and liver fibrosis (NCT02217475). Separate cohorts of aged TBI animals were treated with either vehicle or CVC twice daily several hours after injury (Fig. 5a). Using this experimental approach, we observed a significant reduction in the numbers of CD11b+F4/80+CD45hiLy6C+ macrophages (Fig. 5b,c), which are analogous to CCR2+ macrophages, recruited into the diseased brain [12, 28].Fig. 5

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