title: Ccr2 deletion dissociates cavity size and tau pathology after mild traumatic brain injury.
abstract: BACKGROUND
  Millions of people experience traumatic brain injury (TBI) as a result of falls, car accidents, sports injury, and blast. TBI has been associated with the development of neurodegenerative conditions such as Alzheimer's disease (AD) and chronic traumatic encephalopathy (CTE). In the initial hours and days, the pathology of TBI comprises neuronal injury, breakdown of the blood-brain barrier, and inflammation. At the cellular level, the inflammatory reaction consists of responses by brain-resident microglia, astrocytes, and vascular elements as well as infiltration of peripheral cells. After TBI, signaling by chemokine (C-C motif) ligand 2 (CCL2) to the chemokine (C-C motif) receptor 2 (CCR2) is a key regulator of brain infiltration by monocytes.
  
  
  METHODS
  We utilized mice with one or both copies of Ccr2 disrupted by red fluorescent protein (RFP, Ccr2 (RFP/+) and Ccr2 (RFP/RFP) ). We subjected these mice to the mild lateral fluid percussion model of TBI and examined several pathological outcomes 3 days later in order to determine the effects of altered monocyte entry into the brain.
  
  
  RESULTS
  Ccr2 deletion reduced monocyte infiltration, diminished lesion cavity volume, and lessened axonal damage after mild TBI, but the microglial reaction to the lesion was not affected. We further examined phosphorylation of the microtubule-associated protein tau, which aggregates in brains of people with TBI, AD, and CTE. Surprisingly, Ccr2 deletion was associated with increased tau mislocalization to the cell body in the cortex and hippocampus by tissue staining and increased levels of phosphorylated tau in the hippocampus by Western blot.
  
  
  CONCLUSIONS
  Disruption of CCR2 enhanced tau pathology and reduced cavity volume in the context of TBI. The data reveal a complex role for CCR2(+) monocytes in TBI, as monitored by cavity volume, axonal damage, and tau phosphorylation.
authors.affiliation: Department of Neurosciences, Lerner Research Institute, Cleveland Clinic Foundation, Cleveland, OH, USA. stefka.gyoneva@biogen.com.|Neuroinflammation Research Center, Cleveland Clinic Foundation, Cleveland, OH, USA. stefka.gyoneva@biogen.com.|Neuroimmunology, Biogen, 225 Binney St, Cambridge, MA, 02142, USA. stefka.gyoneva@biogen.com.
authors.forename: Stefka
authors.initials: S
authors.lastname: Gyoneva
authors.affiliation: Department of Chemistry, Case Western Reserve University, Cleveland, OH, USA. dgk30@case.edu.|Neuroinflammation Research Center, Cleveland Clinic Foundation, Cleveland, OH, USA. dgk30@case.edu.
authors.forename: Daniel
authors.initials: D
authors.lastname: Kim
authors.affiliation: Department of Neurosciences, Lerner Research Institute, Cleveland Clinic Foundation, Cleveland, OH, USA. katsuma@ccf.org.|Neuroinflammation Research Center, Cleveland Clinic Foundation, Cleveland, OH, USA. katsuma@ccf.org.
authors.forename: Atsuko
authors.initials: A
authors.lastname: Katsumoto
authors.affiliation: Department of Neurosciences, Lerner Research Institute, Cleveland Clinic Foundation, Cleveland, OH, USA. kokikoo@ccf.org.|Neuroinflammation Research Center, Cleveland Clinic Foundation, Cleveland, OH, USA. kokikoo@ccf.org.
authors.forename: O Nicole
authors.initials: ON
authors.lastname: Kokiko-Cochran
authors.affiliation: Department of Neurosciences, Lerner Research Institute, Cleveland Clinic Foundation, Cleveland, OH, USA. lambb@ccf.org.|Neuroinflammation Research Center, Cleveland Clinic Foundation, Cleveland, OH, USA. lambb@ccf.org.
authors.forename: Bruce T
authors.initials: BT
authors.lastname: Lamb
authors.affiliation: Department of Neurosciences, Lerner Research Institute, Cleveland Clinic Foundation, Cleveland, OH, USA. richard.ransohoff@biogen.com.|Neuroinflammation Research Center, Cleveland Clinic Foundation, Cleveland, OH, USA. richard.ransohoff@biogen.com.|Neuroimmunology, Biogen, 225 Binney St, Cambridge, MA, 02142, USA. richard.ransohoff@biogen.com.
authors.forename: Richard M
authors.initials: RM
authors.lastname: Ransohoff
mesh_terms: D000818:Animals; D001930:Brain Injuries / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D005260:Female; D017353:Gene Deletion; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D009000:Monocytes / Q000378:metabolism / Q000473:pathology; D054390:Receptors, CCR2 / Q000172:deficiency* / Q000235:genetics; D016875:tau Proteins / Q000235:genetics / Q000378:metabolism*
chemical_list: C515335:Ccr2 protein, mouse; C558298:Mapt protein, mouse; D054390:Receptors, CCR2; D016875:tau Proteins