Microglial/Macrophage Polarization Dynamics following Traumatic Brain Injury

Abstract

Activated microglia and macrophages exert dual beneficial and detrimental roles after central nervous system injury, which are thought to be due to their polarization along a continuum from a classical pro-inflammatory M1-like state to an alternative anti-inflammatory M2-like state. The goal of the present study was to analyze the temporal dynamics of microglia/macrophage polarization within the lesion micro-environment following traumatic brain injury (TBI) using a moderate-level controlled cortical impact (CCI) model in mice. We performed a detailed phenotypic analysis of M1-and M2-like polarized microglia/macrophages, as well as nicotinamide adenine dinucleotide phosphate oxidase (NOX2) expression, through 7 days post-injury using real-time polymerase chain reaction (qPCR), flow cytometry and image analyses. We demonstrated that microglia/macrophages express both M1-and M2-like phenotypic markers early after TBI, but the transient up-regulation of the M2-like phenotype was replaced by a predominant M1-or mixed transitional (Mtran) phenotype that expressed high levels of NOX2 at 7 days post-injury. The shift towards the M1-like and Mtran phenotype was associated with increased cortical and hippocampal neurodegeneration. In a follow up study, we administered a selective NOX2 inhibitor, gp91ds-tat, to CCI mice starting at 24 h post-injury to investigate the relationship between NOX2 and M1-like/Mtran phenotypes. Delayed gp91ds-tat treatment altered M1-/M2-like balance in favor of the anti-inflammatory M2-like phenotype, and significantly reduced oxidative damage in neurons at 7 days post-injury. Therefore, our data suggest that despite M1-like and M2-like polarized microglia/macrophages being activated after TBI, the early M2-like response becomes dysfunctional over time, resulting in development of pathological M1-like and Mtran phenotypes driven by increased NOX2 activity.

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). We and others have shown that blocking the acute inflammatory responses within 24 h after injury prevented the development of TBI-induced cognitive deficits (34,39,40,45,50,56,57).…”

Age-Dependent Responses Following Traumatic Brain Injury

“…Lastly, subtype-specific recruitment of monocytes/macrophages (M1 vs. M2) has also been shown to play a critical role in outcome following CNS injury [102,103]. However, age-dependent effects of these cell types in both acute and chronic TBI outcome have yet to be investigated.…”

Microglia Activation and Polarization After Intracerebral Hemorrhage in Mice: the Role of Protease-Activated Receptor-1

“…Microglia/macrophage activation and M1/M2 polarization have been well characterized in several types of acute central nervous system injury, including traumatic brain injury [16, 17], spinal cord injury [10], and ischemic stroke [11, 18]. Previous studies have revealed that the activation of microglia/macrophages occurs in the hemorrhagic brain and results in inflammatory injury after ICH [1, 7, 19–21].…”