title: Age exacerbates the CCR2/5-mediated neuroinflammatory response to traumatic brain injury.
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.
authors.affiliation: Brain and Spinal Injury Center, University of California, 1001 Potrero Ave, Bldg. 1, Room 101, San Francisco, CA, 94110, USA.|Department of Physical Therapy and Rehabilitation Science, University of California, San Francisco, CA, USA.
authors.forename: Josh M
authors.initials: JM
authors.lastname: Morganti
authors.affiliation: Brain and Spinal Injury Center, University of California, 1001 Potrero Ave, Bldg. 1, Room 101, San Francisco, CA, 94110, USA.
authors.forename: Lara-Kirstie
authors.initials: LK
authors.lastname: Riparip
authors.affiliation: Brain and Spinal Injury Center, University of California, 1001 Potrero Ave, Bldg. 1, Room 101, San Francisco, CA, 94110, USA.|Neuroscience Graduate Program, University of California, San Francisco, CA, USA.
authors.forename: Austin
authors.initials: A
authors.lastname: Chou
authors.affiliation: Department of Neurological Surgery, University of California, San Francisco, CA, USA.
authors.forename: Sharon
authors.initials: S
authors.lastname: Liu
authors.affiliation: Department of Neurological Surgery, University of California, San Francisco, CA, USA.|Department of Pediatrics, University of California, San Francisco, CA, USA.
authors.forename: Nalin
authors.initials: N
authors.lastname: Gupta
authors.affiliation: Brain and Spinal Injury Center, University of California, 1001 Potrero Ave, Bldg. 1, Room 101, San Francisco, CA, 94110, USA. susanna.rosi@ucsf.edu.|Department of Physical Therapy and Rehabilitation Science, University of California, San Francisco, CA, USA. susanna.rosi@ucsf.edu.|Neuroscience Graduate Program, University of California, San Francisco, CA, USA. susanna.rosi@ucsf.edu.|Department of Neurological Surgery, University of California, San Francisco, CA, USA. susanna.rosi@ucsf.edu.
authors.forename: Susanna
authors.initials: S
authors.lastname: Rosi
mesh_terms: D000375:Aging / Q000276:immunology / Q000378:metabolism / Q000473:pathology*; D000818:Animals; D000070642:Brain Injuries, Traumatic / Q000276:immunology / Q000378:metabolism / Q000473:pathology*; D016000:Cluster Analysis; D004195:Disease Models, Animal; D005260:Female; D005434:Flow Cytometry; D007249:Inflammation / Q000276:immunology / Q000378:metabolism / Q000473:pathology*; D008264:Macrophages / Q000473:pathology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D060888:Real-Time Polymerase Chain Reaction; D054390:Receptors, CCR2 / Q000378:metabolism; D019713:Receptors, CCR5 / Q000378:metabolism
chemical_list: C000592874:CCR5 protein, mouse; C515335:Ccr2 protein, mouse; D054390:Receptors, CCR2; D019713:Receptors, CCR5
keywords: Aging; Antagonist; CCR2; Chemokine; Macrophage; Microglia; Neurotrauma