CCR2 deficiency impairs macrophage infiltration and improves cognitive function after traumatic brain injury


Dr. Christine Linda Hsieh, Mrs. Erene C. Niemi, Ms. Sarah H Wang, Mr. Chih Cheng Lee, Dr. Deborah Bingham, Dr. Jiasheng Zhang, Dr. Myrna Cozen, Dr. Israel F. Charo, Dr. Eric J. Huang, Dr. Jialing Liu, and Dr. Mary C. Nakamura


Traumatic brain injury (TBI) provokes inflammatory responses including a dramatic rise in brain macrophages in the area of injury. The pathway(s) responsible for macrophage infiltration of the traumatically injured brain and the effects of macrophages on functional outcomes are not well understood. CCR2 is a chemokine receptor, known for directing monocytes to inflamed tissues. To assess the role of macrophages and CCR2 in TBI, we determined outcomes in Ccr2-/- mice in a controlled cortical impact model. We quantified brain myeloid cell numbers post-TBI by flow cytometry and found that Ccr2-/- mice had greatly reduced macrophage numbers (~80-90% reduction) early post-TBI compared to wild type mice. Motor, locomotor, and cognitive outcomes were assessed in Ccr2-/- mice following TBI. Lack of Ccr2 improved locomotor activity with less hyperactivity in open field testing, but did not affect anxiety levels or motor coordination on the rotor rod 3 weeks after TBI. Importantly, Ccr2-/- mice demonstrated greater spatial learning and memory compared to wild type mice eight weeks after TBI. Although there was no difference in the volume of tissue loss, Ccr2-/- mice had significantly increased neuronal density in the CA1-CA3 regions of the hippocampus after TBI compared to wild type mice. These data demonstrate that Ccr2 directs the majority of macrophage homing to the brain early after TBI and indicates that Ccr2 may facilitate harmful responses. Lack of Ccr2 improves functional recovery and neuronal survival. These results suggest that therapeutic blockade of CCR2-dependent responses may improve outcomes following TBI.