Abstract
Traumatic brain injury (TBI) is associated with poor clinical outcomes; autopsy studies of TBI victims demonstrate significant oligodendrocyte progenitor cell (OPC) death post TBI; an observation, which may explain the lack of meaningful repair of injured axons. Whilst high-mobility group box-1 (HMGB1) and its key receptors TLR2/4 are identified as key initiators of neuroinflammation post-TBI, they have been identified as attractive targets for development of novel therapeutic approaches to improve post-TBI clinical outcomes. In this report we establish unequivocal evidence that HMGB1 released in vitro impairs OPC response to mechanical injury; an effect that is pharmacologically reversible. We show that needle scratch injury hyper-acutely induced microglial HMGB1 nucleus-to-cytoplasm translocation and subsequent release into culture medium. Application of injury-conditioned media resulted in significant decreases in OPC number through anti-proliferative effects. This effect was reversed by co-treatment with the TLR2/4 receptor antagonist BoxA. Furthermore, whilst injury conditioned medium drove OPCs towards an activated reactive morphology, this was also abolished after BoxA co-treatment. We conclude that HMGB1, through TLR2/4 dependant mechanisms, may be detrimental to OPC proliferation following injury in vitro, negatively affecting the potential for restoring a mature oligodendrocyte population, and subsequent axonal remyelination. Further study is required to assess how HMGB1-TLR signalling influences OPC maturation and myelination capacity.
Highlights
Traumatic brain injury (TBI) is associated with poor clinical outcomes; autopsy studies of TBI victims demonstrate significant oligodendrocyte progenitor cell (OPC) death post TBI; an observation, which may explain the lack of meaningful repair of injured axons
Examining the differential cell subtype contribution to high-mobility group box-1 (HMGB1) activation, we found a significant increase in proportions of microglia (Ib4+) cells with cytoplasmic HMGB1 (25.3 ± 7.2 vs 9.8 ± 4.2% relative to control, p = 0.003)
It is possible that the impacts we report of HMGB1 upon Neurone Glia 2 (NG2)+ cells may be mediated via other cells present in our cultures, such as astrocytes or microglia
Summary
Traumatic brain injury (TBI) is associated with poor clinical outcomes; autopsy studies of TBI victims demonstrate significant oligodendrocyte progenitor cell (OPC) death post TBI; an observation, which may explain the lack of meaningful repair of injured axons. Application of injury-conditioned media resulted in significant decreases in OPC number through anti-proliferative effects This effect was reversed by co-treatment with the TLR2/4 receptor antagonist BoxA. Recent studies have identified high mobility group box-1 (HMGB1), as a protein that propagates inflammation following TBI3,6. It is one of the ‘damage associated molecular pattern’ (DAMP) molecules, which stimulate the release of the pro- neuroinflammatory factors described above[6]. The receptor for advanced glycation end products (RAGE)[8,9] These pathways may be mediators of brain damage after TBI, and could potentially be amenable to therapeutic modulation
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