Pre-injury monocyte/macrophage depletion results in increased blood-brain barrier permeability after traumatic brain injury.

Abstract

Traumatic brain injury (TBI) effects both the brain and the immune system. Circulating monocytes/macrophages (Mo /Ma ) after a TBI may play an important role in preserving the blood-brain barrier (BBB), reducing brain edema, and interacting with resident microglia. To elucidate the role of circulating Mo /Ma , we utilized a monocyte/macrophage depletion model in response to TBI in male rats. Clodronate liposomes (CL) were used to deplete circulating Mo /Ma . A controlled cortical impact (CCI) injury model was used to create a TBI. All animals received either CL or PBS liposomes (PL), 48 and 24hr prior to the procedure, and were sacrificed 72hr post-injury for analysis of BBB permeability, brain edema, whole blood (Mo /Ma and granulocytes), and/or microglial analysis. Animals undergoing Mo /Ma depletion with CL prior to CCI (CCI-CL) were found to have increased BBB permeability when compared to non-depleted CCI (CCI-PL) animals. At 72hr following injury, Sham-CL maintained on average an 82% reduction in the whole blood monocytes when compared to Sham-PL (p<0.001). Monocytes in the whole blood remained significantly lower in CCI-CL animals when compared to CCI-PL (p<0.001). The number of granulocytes in the whole blood of CCI-CL animals was higher at 3days when compared to CCI-PL (p<0.022). Surprisingly, the depletion of Mo /Ma did not affect brain edema. However, the depletion of Mo /Ma did result in a significant decrease in microglia (CCI-CL vs. CCI-PL, p<0.012). In conclusion, an intact Mo /Ma population is required to repair BBB integrity and microglial response following injury.