Abstract
Brain trauma is known to activate inflammatory cells via various chemokine signals although their interactions remain to be characterized. Mice deficient in Ccl3, Ccr2 or Cxcl10 were compared with wildtype mice after controlled cortical impact injury. Expression of Ccl3 in wildtypes was rapidly upregulated in resident, regularly spaced reactive microglia. Ccl3-deficiency enhanced endothelial expression of platelet selectin and invasion of peripheral inflammatory cells. Appearance of Ccr2 transcripts, encoding the Ccl2 receptor, reflected invasion of lysozyme 2-expressing phagocytes and classical antigen-presenting dendritic cells expressing major histocompatibility complex class II. Ccr2 also directed clustered plasmacytoid dendritic cells positive for the T-cell attracting chemokine Cxcl10. A reduction in Ccr2 and dendritic cells was found in injured wildtype cortex after cyclophosphamide treatment resembling effects of Ccr2-deficiency. The findings demonstrate the feasibility to control inflammation in the injured brain by regulating chemokine-dependent pathways.
Highlights
Traumatic brain injury (TBI) in mice results in distinct upregulation of hundreds of gene transcripts including many linked to inflammation [1,2]
We have previously described the appearance of clustered inflammatory cells expressing chemokine Cxcl10 scattered in grey and white matter of injured wildtype brains using a controlled cortical impact (CCI) injury model [1,2,7,8]
The present findings confirm that interactions among chemokines in the injured brain set the stage for inflammatory cell activation
Summary
Traumatic brain injury (TBI) in mice results in distinct upregulation of hundreds of gene transcripts including many linked to inflammation [1,2]. The inflammatory cascade activated by TBI lacks specific pharmacological treatments and is elicited by mechanisms including reactive oxygen species (ROS), hemorrhage and release of nucleotides sensed by upregulated pyrimidinergic receptors such as P2ry6 [1]. This suggests postinjury chemokine functions in brain tissue the interactions among different chemokines, cellular sources of signals and targets for signaling remain unknown. A model for hierarchical chemokine activities in the injured cerebral cortex is currently presented
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