The roles of the alarmin HMGB1 in injury and repair of white matter after traumatic brain injury

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White matter injury is increasingly recognised as a key hallmark of traumatic brain injury (TBI), this type of injury is particularly associated with poor clinical outcome1. Autopsy studies of TBI victims demonstrate significant oligodendrocyte cell death post TBI, and white matter integrity is linked to both motor and psychological recovery after injury to the central nervous system (1,2). Whilst neurone injury and axonal loss are undoubtedly contributary to death and disability post-neurotrauma, loss of myelinating cells, oligodendrocytes, and failure of repair of myelination of surviving axons has been demonstrated to correlate with neurological disability after TBI (2,3). Recently, HMGB1 (High-mobility group box 1 protein), has emerged as a key initiator of brain inflammation after TBI (1). HMGB1-mediated pathways are thus attractive targets for the development of novel therapeutic approaches to protect and repair white matter after brain trauma (1,3). We have recently identified HMGB1 as a key neuroinflammatory mediator that decreased neuronal survival and oligodendroglial cell proliferation and differentiation after injury in rats. These observations are relevant as the loss of white matter and myelination after TBI may be explained by a) direct oligodendrocyte death after TBI, and/or b) impaired proliferation or maturation of oligodendroglial progenitors following neurotrauma, (4) leading to a lack of meaningful remyelination of surviving axons. Oligodendrocytes themselves are exquisitely sensitive to noxious stimuli, (2) and protection and support of their progenitors has emerged as an attractive strategy to support remyelination following injury to the central nervous system (4). In this proposal we intend to validate these findings in a drop-weight 3D human cortical cell culture model. This novel experimental approach will allow us to probe the impacts of neurotrauma upon human oligodendroglial cells, which is yet to be investigated in the existing literature, and test how these responses might be manipulated through immunomodulation of HMGB1-mediated signalling, and/or other related damage-associated-molecular-pattern (DAMP) mediated pathways. This may lead to the identification of novel pathways which may be amenable to pharmacological modulation to improve outcomes for TBI patients. Several pharmacological agents acting upon the HMGB1-signalled axis are already in clinical use/undergoing phase 2-3 trials in other neuropathological patient cohorts, and so if this pathway is identified as a potential modulator of white matter injury and repair after TBI in this fellowship, there is the potential for rapid clinical translation. The proposed studentship's assessment of these pathways in a human tissue models of TBI is a novel component of the proposal which is yet to assessed in the existing literature. 1.Parker et al. The danger zone: Systematic review of the role of HMGB1 danger signalling in traumatic brain injury. Brain Inj 31, 2-8, (2017)2. Dent et al. Oligodendrocyte birth and death following traumatic brain injury in adult mice. PLoS One 10 (2015)3. Armstrong et al. Myelin and oligodendrocyte lineage cells in white matter pathology and plasticity after traumatic brain injury. Neuropharmacology. 110: 654-659 (2016)4. Veronique et al. Cells of the oligodendroglial lineage, myelination, and remyelination. Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease, 1812, 184-193 (2011)5. Marmarou et al. (eds) Animal Models of Acute Neurological Injuries. Springer Protocols Handbooks. Humana Press. (2009)