CCR2 Deficiency Impairs Macrophage Infiltration and Improves Cognitive Function after Traumatic Brain Injury

Abstract

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. C-C-chemokine receptor 2 (CCR2) is known for directing monocytes to inflamed tissues. To assess the role of macrophages and CCR2 in TBI, we determined outcomes in CCR2-deficient (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 with wild-type mice. Motor, locomotor, and cognitive outcomes were assessed. Lack of Ccr2 improved locomotor activity with less hyperactivity in open field testing, but did not affect anxiety levels or motor coordination on the rotarod three weeks after TBI. Importantly, Ccr2-/ -mice demonstrated greater spatial learning and memory, compared with wildtype 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 with 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.

Performance of Male and Female C57BL/6J Mice on Motor and Cognitive Tasks Commonly Used in Pre-Clinical Traumatic Brain Injury Research

“…58 Mild or severe traumatic brain injury induces hyperactivity in male and female mice Significant hyperactive exploration in the OF is a frequently reported effect of CCI delivered over parietal cortex in mice. 33,[59][60][61][62][63] In the current experiment, hyperactivity in injured mice ( Fig. 2A,B) was the result of more-continuous exploration in mice with TBI (fewer starts and stops; Fig.…”

“…3C,D), corroborating previous findings in C57BL/6 mice when tested in an OF after parietal CCI. 33,59,62 However, testing of anxiety in the classic elevated plus maze (EPM) post-TBI yields disparate results. Washington and colleagues 72 reported that cortically injured mice spent a greater amount of time in anxiogenic regions of the EPM on the 20th day postinjury and concluded that brain injury results in increased ''risk-taking'' behaviors in mice.…”

Inhibition of the integrated stress response reverses cognitive deficits after traumatic brain injury

“…Previous work has been limited to acute injury responses immediately following injury where a robust inflammatory response characterized by immunecell infiltration into the brain (34,(43)(44)(45)(46)(47), cytokine production (39,40,(48)(49)(50), and reactive oxygen species release (51-53) lead to neuronal death. Thus, strategies to counteract acute injurymediated effects have aimed to dampen the inflammatory response (43,44,52,54,55).…”

Microglial/Macrophage Polarization Dynamics following Traumatic Brain Injury

“…Compared with wild-type mice, CCR2 knockout mice subjected to CCI have reduced lesion volumes, decreased pro-inflammatory gene expression, decreased macrophage infiltration in the injured cortex and improved cognitive function recovery after TBI. 32,33 Morganti and colleagues recently evaluated a CCR2 antagonist (CCX872) in CX3CR1GFP/+CCR2RFP/+ reporter mice using the 34 CCR2 antagonism also improved cognitive function recovery after TBI, as demonstrated by increased performance of CCX872-treated mice in a radial arm water maze test at 28 days post-injury. 34 They also showed that CCR2-positive infiltrating macrophages in the brain expressed both M1-and M2-like markers acutely after TBI, with sequential activation of M1-, followed by M2a-, and finally M2c-marker expression.…”