Polarization of Microglia to the M2 Phenotype in a Peroxisome Proliferator-Activated Receptor Gamma-Dependent Manner Attenuates Axonal Injury Induced by Traumatic Brain Injury in Mice.

Increasing evidence indicates that activated microglia play an important role in the inflammatory response following traumatic brain injury (TBI). Inhibiting M1 and stimulating M2 activated microglia have demonstrated protective effects in several animal models of central nervous system diseases. However, it is not clear whether the polarization of microglia to M2 attenuates axonal injury following TBI. In this study, we used a lateral fluid percussion injury device to induce axonal injury in mice. Mice were randomly assigned to the sham, TBI, TBI + rosiglitazone (peroxisome proliferator-activated receptor gamma [PPAR-γ] agonist), and TBI + GW9662 (PPAR-γ antagonist) groups. Axonal injury was assessed using immunohistochemical staining for beta amyloid precursor protein. The inflammatory response was assessed by enzyme-linked immunosorbent assay, microglia polarization was assessed using specific markers of M1 and M2 microglia, and neurological function was assessed using the neurological severity score. Following TBI, microglia of the M1 phenotype increased significantly, while those of the M2 phenotype decreased. Rosiglitazone-induced PPAR-γ activation promoted microglia polarization to the M2 phenotype, which reduced the inflammatory response, attenuated axonal injury in the cerebral cortex, and improved neurological function. Conversely, GW9662 inhibited the polarization of microglia to M2 and aggravated inflammation and axonal injury. Our in vitro findings in lipopolysaccharide-induced microglia were consistent with those of our in vivo experiments. In conclusion, the polarization of microglia to the M2 phenotype via PPAR-γ activation attenuated axonal injury following TBI in mice, which may be a potential therapeutic approach for TBI-induced axonal injury.

Cell activation and inflammatory response following traumatic axonal injury in the rat.

In a rat model of traumatic brain injury cell activation was characterized immunohistochemically from 2 h up to 2 weeks. Reactive astrocytosis became apparent perivascularly and in the grey matter within 4h after trauma. Increased OX42 immunoreactivity indicated microglial activation in cortex and hippocampus as early as 4 h, whereas up-regulation of MHC class II (OX6) was evident in white matter tracts at 24 h. Although macrophage (ED1) numbers increased in the meninges and perivascularly, brain infiltration appeared marginal. Accumulation of lymphocytes and granulocytes was not observed. Our results show that traumatic axonal injury induces a rapid and sustained glial activation in the absence of leukocyte infiltration. Thus, cell activation following diffuse trauma strongly differs from that found after focal brain damage, awaiting further functional characterization.