Disulfide HMGB1 acts via TLR2/4 receptors to reduce the numbers of oligodendrocyte progenitor cells after traumatic injury in vitro

• Published in: Scientific reports Vol. 11; no. 1; p. 6181
• Main Authors: Ved, R, Sharouf, F, Harari, B, Muzaffar, M, Manivannan, S, Ormonde, C, Gray, W P, Zaben, M
• Format: Journal Article
• Language: English
• Published: England Nature Publishing Group 17.03.2021; Nature Publishing Group UK; Nature Portfolio
• Subjects: Animals; Autopsy; Brain Injuries, Traumatic - metabolism; Cell culture; Cell death; Clinical outcomes; Cytoplasm; Glial stem cells; HMGB1 protein; HMGB1 Protein - metabolism; Inflammation; Maturation; Myelination; Oligodendrocyte Precursor Cells - cytology; Oligodendrocyte Precursor Cells - metabolism; Progenitor cells; Rats; Rats, Sprague-Dawley; TLR2 protein; Toll-Like Receptor 2 - metabolism; Toll-Like Receptor 4 - metabolism; Toll-like receptors; Translocation; Traumatic brain injury
• ISSN: 2045-2322; 2045-2322
• DOI: 10.1038/s41598-021-84932-0

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.