High mobility group box protein‐1 promotes cerebral edema after traumatic brain injury via activation of toll‐like receptor 4

Abstract

Traumatic brain injury (TBI) is a major cause of mortality and morbidity worldwide. Cerebral edema, a life-threatening medical complication, contributes to elevated intracranial pressure (ICP) and a poor clinical prognosis after TBI. Unfortunately, treatment options to reduce post-traumatic edema remain suboptimal, due in part, to a dearth of viable therapeutic targets. Herein, we tested the hypothesis that cerebral innate immune responses contribute to edema development after TBI. Our results demonstrate that high-mobility group box protein 1 (HMGB1) was released from necrotic neurons via a NR2B-mediated mechanism. HMGB1 was clinically associated with elevated ICP in patients and functionally promoted cerebral edema after TBI in mice. The detrimental effects of HMGB1 were mediated, at least in part, via activation of microglial toll-like receptor-4 (TLR4) and the subsequent expression of the astrocytic water channel, aquaporin-4 (AQP4). Genetic or pharmacological (VGX-1027) TLR4 inhibition attenuated the neuroinflammatory response and limited post-traumatic edema with a delayed, clinically implementable therapeutic window. Human and rodent tissue culture studies further defined the cellular mechanisms demonstrating neuronal HMGB1 initiates the microglial release of interleukin-6 (IL-6) in a TLR4 dependent mechanism. In turn, microglial IL-6 increased the astrocytic expression of AQP4. Taken together, these data implicate microglia as key mediators of post-traumatic brain edema and suggest HMGB1-TLR4 signaling promotes neurovascular dysfunction after TBI.

High Mobility Group Box 1 and Traumatic Brain Injury

“…The traumatic events leading to the secretion of HMGB1 into the CSF also initiate the secretion of other DAMP into the CSF with successive activation of the innate immune response [25]. Laird et al demonstrated that HMGB1 displayed a supreme neuronal localization within the mouse cerebral cortex and reduce immunoreactivity for HMGB1 was temporally associated with the loss of NeuN within the peri-contusional cortex, suggesting HMGB1 was released by injured neurons into the extracellular space after TBI [27].…”

“…It has been observed that, over-stimulation of N-methyl-D-aspartate receptors (NMDA-R) by raised extracellular glutamate generate excitotoxicity, an important initiator of neuronal necrosis and edema after TBI [27] [29]. Studies have further demonstrated NMDA-R exist as a tetrameric protein receptor complex made up of two glycine-binding NR1 subunits and two glutamate-binding NR2 subunits that ascertain the biophysical properties [27] [30].…”

“…Studies have further demonstrated NMDA-R exist as a tetrameric protein receptor complex made up of two glycine-binding NR1 subunits and two glutamate-binding NR2 subunits that ascertain the biophysical properties [27] [30].…”

“…They further demonstrated that activation of NR2B bolsters neuronal injury and accelerates neuronal HMGB1 release ( Figure 1) to augment brain swelling, although the mechanism is still not well understood [27]. Bohmer and colleagues have indicated that there is accumulation of HMGB1 and Neuron-specific Enolase (NSE) within the CSF of neurotrauma patients.…”

“…Activation of NR2B promotes neuronal injury and increases neuronal HMGB1 release. HMGB1 binds to TLR4 receipts thereby regulating AQP-4 and promotion of cerebral edema [27]. in a sense that its effects are interconnected and affect many target cells in vivo, and that this multi-functionality and complexity may result in serious brain damage [12].…”