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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.

Age exacerbates the CCR2/5-mediated neuroinflammatory response to traumatic brain injury