Microglia/Macrophage Polarization Dynamics in White Matter after Traumatic Brain Injury

Abstract

Mononuclear phagocytes are a population of multi-phenotypic cells and have dual roles in brain destruction/reconstruction. The phenotype-specific roles of microglia/macrophages in traumatic brain injury (TBI) are, however, poorly characterized. In the present study, TBI was induced in mice by a controlled cortical impact (CCI) and animals were killed at 1 to 14 days post injury. Real-time polymerase chain reaction (RT-PCR) and immunofluorescence staining for M1 and M2 markers were performed to characterize phenotypic changes of microglia/macrophages in both gray and white matter. We found that the number of M1-like phagocytes increased in cortex, striatum and corpus callosum (CC) during the first week and remained elevated until at least 14 days after TBI. In contrast, M2-like microglia/macrophages peaked at 5 days, but decreased rapidly thereafter. Notably, the severity of white matter injury (WMI), manifested by immunohistochemical staining for neurofilament SMI-32, was strongly correlated with the number of M1-like phagocytes. In vitro experiments using a conditioned medium transfer system confirmed that M1 microglia-conditioned media exacerbated oxygen glucose deprivation-induced oligodendrocyte death. Our results indicate that microglia/macrophages respond dynamically to TBI, experiencing a transient M2 phenotype followed by a shift to the M1 phenotype. The M1 phenotypic shift may propel WMI progression and represents a rational target for TBI treatment.

HDAC inhibition prevents white matter injury by modulating microglia/macrophage polarization through the GSK3β/PTEN/Akt axis

“…Nonetheless, it is known that oligodendrocytes are especially vulnerable to mechanical trauma (10,26,27), and that neuroinflammation may exacerbate WMI following TBI (15,21). The present study improves our understanding of white matter pathophysiology by showing that microglia/macrophages exert protective or destructive effects on oligodendrocytes depending on M2 or M1 polarization status, respectively.…”

“…In contrast, the M2 phenotype promotes the release of neurotrophic factors that promote neurorepair (18,20). We recently showed that M1 conditioned medium (CM) enhances oligodendrocyte cell death in vitro following oxygen glucose deprivation (OGD), whereas M2 CM is protective (19,21). In the same study, we Significance Moderate or severe traumatic brain injury (TBI) damages white matter, thereby contributing to long-term neurological deficits.…”

“…These results reveal a previously unexplored role for GSK3β/PTEN/PI3K signaling in the regulation of microglia/macrophages and demonstrate the promise of HDAC inhibition in the treatment of TBI/WMI. found that microglia/macrophages respond to TBI with a transient M2 phenotype, followed by a shift to M1, and that the number of M1 cells is strongly correlated with the severity of WMI (21). Thus, therapies that prime microglia/macrophages toward the beneficial M2 phenotype after TBI may offer new anti-inflammatory strategies to protect against WMI.…”

Targeting resolution of neuroinflammation after ischemic stroke with a lipoxin A4 analog: Protective mechanisms and long‐term effects on neurological recovery

“…The receptor CD40 is a marker of M1 cells, as cytokine binding (such as TNF‐α) and its ligand CD40L can lead to the activation of inflammatory pathways and result in the formation of ROS, pro‐inflammatory cytokines and chemokines, and the upregulation of adhesion molecules on endothelial cells (Benveniste, Nguyen, & Wesemann, 2004; Tan et al., 1999). In the post‐ischemic brain and after traumatic brain injury, recent studies from the same laboratory have reported a low population of M1 cells a few days after injury that gradually increases and peaks by 7–14 days (Hu et al., 2012; Wang et al., 2013). Another study reported no significant difference between levels of CD40 in a sham mouse and a mouse 3 days after ischemic stroke (Gelderblom et al., 2009).…”

Erythropoietin regulates immune/inflammatory reaction and improves neurological function outcomes in traumatic brain injury

“…Later, CD3 + T cells secrete large amounts of proinflammatory cytokines, which exasperate secondary brain injury. In TBI, there is always excessive activation of microglia, which participate in the antigen presentation and promote neuron apoptosis (Wang et al., 2013). In this study, we demonstrated that EPO treatment decreased the activated microglia expression in the cortex of injured brain.…”