Time-Dependent Changes in Microglia Transcriptional Networks Following Traumatic Brain Injury

Abstract

The neuroinflammatory response to traumatic brain injury (TBI) is critical to both neurotoxicity and neuroprotection, and has been proposed as a potentially modifiable driver of secondary injury in animal and human studies. Attempts to broadly target immune activation have been unsuccessful in improving outcomes, in part because the precise cellular and molecular mechanisms driving injury and outcome at acute, subacute, and chronic time points after TBI remain poorly defined. Microglia play a critical role in neuroinflammation and their persistent activation may contribute to long-term functional deficits. Activated microglia are characterized by morphological transformation and transcriptomic changes associated with specific inflammatory states. We analyzed the temporal course of changes in inflammatory genes of microglia isolated from injured brains at 2, 14, and 60 days after controlled cortical impact (CCI) in mice, a well-established model of focal cerebral contusion. We identified a time dependent, injury-associated change in the microglial gene expression profile toward a reduced ability to sense tissue damage, perform housekeeping, and maintain homeostasis in the early stages following CCI, with recovery and transition to a specialized inflammatory state over time. This later state starts at 14 days post-injury and is characterized by a biphasic pattern of IFNγ, IL-4, and IL-10 gene expression changes, with concurrent proinflammatory and anti-inflammatory gene changes. Our transcriptomic data sets are an important step to understand microglial role in TBI pathogenesis at the molecular level and identify common pathways that affect outcome. More studies to evaluate gene expression at the single cell level and focusing on subacute and chronic timepoint are warranted.

Fast microglial activation after severe traumatic brain injuries

“…These microglial changes could not only be easily examined with standard histological and immunohistochemical methods but also be used for daily forensic wound age estimation of TBI. A transformation in microglial protein expression towards a more reactive phenotype was also shown in transcriptional studies in rodents after a post-traumatic time course of 2 to 14 days [ 17 ].…”

Repetitive Traumatic Brain Injury Causes Neuroinflammation before Tau Pathology in Adolescent P301S Mice

“…Microglial and astrocyte activation has been reported at acute and chronic time points post-TBI, as these cells play a pivotal role in the brain’s response to injury [ 34 , 54 , 55 ]. Previous studies have also shown evidence of microglial cell activation in adult humanized Tau mice (hTau) at acute and chronic time points post rCHI [ 19 ].…”

Protective Microglial Subset in Development, Aging, and Disease: Lessons From Transcriptomic Studies

“…Interestingly, in an SCI transcriptomic study, a profile of microglia reminiscent of the CD11c+ phenotype was identified (with upregulation of Gpnmb, Spp1, Lpl, Apoe, Igf1, Lgals3, and Itgax among others) and persisted in a full transection model, whereas it contracted concomitantly to recovery in a hemisection model (135), indicative of the transitory nature of this subset. Conversely, in TBI, the microglial signature was further from the CD11c+ microglia signature, although Itgax was among the upregulated genes 14 and 60 days post-injury, possibly indicating once again a dilution of the signature in all microglia (136). In addition, considering the difficulty associated with gating out macrophages from microglia in a context of extensive infiltration, macrophage contamination of the sorted samples cannot be excluded in these studies, potentially complicating interpretation of the observed transcriptomes.…”