Divergent Regulation of Macrophage-Mediated Wound Repair Following Mild Traumatic Brain Injury
Russo, Matthew V
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Mild traumatic brain injuries (mTBI) often cause meningeal vascular injury and cell death that can spread into the brain parenchyma. This triggers a local inflammatory response that fosters the recruitment of peripheral immune cells, including neutrophils and both subsets of blood monocytes (classical and non-classical). The regenerative capacity of the meninges as well as the factors that dictate the recovery trajectory following mTBI are presently unknown. Most mTBI patients resolve their meningeal vascular damage within 2-3 weeks, although the injury persists in a subset of patients for months. Using a closed-skull compression model of mTBI, we found that meningeal vasculature can regenerate within 7 days of injury, coinciding with a dynamic, bifurcated myeloid cell response. Both inflammatory classical monocytes and non-classical monocytes from the blood swarmed the meninges 1 day after injury followed by an accumulation of CX3CR1+ macrophages over the ensuing 4-7 days. Wound-healing CD206+ macrophages preferentially located around the perimeter of the lesion in close proximity to regenerating blood vessels while CD206- myeloid cells localized to the lesion core. Peripheral depletion of neutrophils and classical monocytes increased pathology due to inefficient dead cell clearance, but re-vascularization of the wound was not affected. Interestingly, vascular regeneration was significantly impaired only when non-classical monocytes were depleted, resulting in a reduction of CD206+ macrophages specifically around the perimeter of the lesion. These macrophages promoted angiogenesis through fibrin clearance and matrix metalloproteinase 2 production. Together, these studies demonstrate that neutrophils, monocytes, and resident macrophages participate in coordinated yet divergent wound-healing responses to mTBI. Complications such as repetitive head injuries or viral infections following mTBI have the potential to significantly alter the immune response and impact wound repair. To understand the effects of repetitive insults on CNS repair, a secondary injury was applied at either an inflammatory (day 1) or wound-healing (day 4) time-point. Interestingly, a secondary injury experienced during the acute inflammatory, but not the wound-healing, phase aborted this angiogenic repair program and enhanced inflammation following mTBI. No structural damage or macrophage cell death was observed following re-injury at the day 4 time-point. A peripheral infection by lymphocytic choriomeningitis virus (LCMV) during peak vascular damage delayed wound repair and promoted a significant meningeal CD8+ T cell response. Structural damage to the meninges / glia limitans barrier, allowed CD8+ T cells to enter the brain parenchyma where activated microglia upregulated CD11c. The infected environment also shifted the myeloid cells to a more inflammatory state, reducing the amount of CD206+ macrophages around the lesion. These changes ultimately led to a global suppression of angiogenesis-related genes in the presence of LCMV, most notably vascular endothelial growth factor (VEGF) A and its receptor VEGFR2. Taken together, these findings demonstrate that meningeal vasculature can efficiently regenerate after injury due to robust inflammatory and wound-healing immune responses. However, this wound repair can be significantly disrupted by both sterile and viral insults following the initial injury.