Blast exposure causes dynamic microglial/macrophage responses and microdomains of brain microvessel dysfunction

Abstract

Exposure to blast overpressure (BOP) is associated with behavioral, cognitive, and neuroimaging abnormalities. We investigated the dynamic responses of cortical vasculature and its relation to microglia/macrophage activation in mice using intravital two-photon microscopy following mild blast exposure. We found that blast caused vascular dysfunction evidenced by microdomains of aberrant vascular permeability. Microglial/macrophage activation was specifically associated with these restricted microdomains, as evidenced by rapid microglial process retraction, increased amoeboid morphology, and escape of blood-borne Q-dot tracers that were internalized in microglial/macrophage cell bodies and phagosome-like compartments. Microdomains of cortical vascular disruption and microglial/macrophage activation were also associated with aberrant tight junction morphology that was more prominent after repetitive (3X) blast exposure. Repetitive, but not single, BOPs also caused TNFα elevation two weeks post-blast. In addition, following a single BOP we found that aberrantly phosphorylated tau rapidly accumulated in perivascular domains, but cleared within four hours, suggesting it was removed from the perivascular area, degraded, and/or dephosphorylated. Taken together these findings argue that mild blast exposure causes an evolving CNS insult that is initiated by discrete disturbances of vascular function, thereby setting the stage for more protracted and more widespread neuroinflammatory responses.

Rapid neuroinflammatory response localized to injured neurons after diffuse traumatic brain injury in swine

“…Recent investigations of microglial behavior after rodent models of closed-head TBI suggest that microglia change morphology, may prevent parenchymal cell death within the first 12 hours after injury, and colocalize with debris escaping from leaky vasculature (Huber et al, 2016; Roth et al, 2014). Building on these findings, we utilized a single-cell analysis methodology and observed a shift toward a more reactive, amoeboid morphology in microglia localized to damaged neurons but did not observe reactive microglia morphology in regions absent neuronal damage.…”

Lack of chronic neuroinflammation in the absence of focal hemorrhage in a rat model of low-energy blast-induced TBI

“…The lack of inflammation observed in our animals indicates that low-energy blast exposures (74.5 kPa) are not always sufficient to sustain chronic neuroinflammation. In a murine model system, microglial activation associated with microdomains of vascular disruption (tight junction injury) has been observed 45 min post 105.5-kPa blast exposure [22]. However, by 14 days post-blast, elevated levels of TNF-α were only sustained in animals exposed to three repetitive blasts, suggesting that even at higher blast energy, repetitive exposures are required to promote more persistent neuroinflammatory changes in the CNS [22].…”

“…In a murine model system, microglial activation associated with microdomains of vascular disruption (tight junction injury) has been observed 45 min post 105.5-kPa blast exposure [22]. However, by 14 days post-blast, elevated levels of TNF-α were only sustained in animals exposed to three repetitive blasts, suggesting that even at higher blast energy, repetitive exposures are required to promote more persistent neuroinflammatory changes in the CNS [22]. In blast-induced TBI, vascular blood leakage may be a requirement for the progression and persistence of neuroinflammation.…”

Distinguishing the Unique Neuropathological Profile of Blast Polytrauma

“…An antibody, like CD68, would be more sensitive as it has a distinct role in phagocytosis during the activation process. There is a potential that microglia at seven days after blast are in a retracted process activation state [41] and this morphology would be difficult to quantify with IBA-1.…”