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High-mobility group box-1 as an autocrine trophic factor in white matter stroke

Authors
Choi, JY  | Cui, Y  | Chowdhury, ST | Kim, BG
Citation
Proceedings of the National Academy of Sciences of the United States of America, 114(25). : E4987-E4995, 2017
Journal Title
Proceedings of the National Academy of Sciences of the United States of America
ISSN
0027-84241091-6490
Abstract
Maintenance of white matter integrity in health and disease is critical for a variety of neural functions. Ischemic stroke in the white matter frequently results in degeneration of oligodendrocytes (OLs) and myelin. Previously, we found that toll-like receptor 2 (TLR2) expressed in OLs provides cell-autonomous protective effects on ischemic OL death and demyelination in white matter stroke. Here, we identified high-mobility group box-1 (HMGB1) as an endogenous TLR2 ligand that promotes survival of OLs under ischemic stress. HMGB1 rapidly accumulated in the culture medium of OLs exposed to oxygen-glucose deprivation (OGD). This conditioned medium exhibited a protective activity against ischemic OL death that was completely abolished by immunodepletion of HMGB1. Knockdown of HMGB1 or application of glycyrrhizin, a specific HMGB1 inhibitor, aggravated OGD-induced OL death, and recombinant HMGB1 application reduced the extent of OL death in a TLR2-dependent manner. We confirmed that cytosolic translocation of HMGB1 and activation of TLR2-mediated signaling pathways occurred in a focal white matter stroke model induced by endothelin-1 injection. Animals with glycyrrhizin coinjection showed an expansion of the demyelinating lesion in a TLR2-dependent manner, accompanied by aggravation of sensorimotor behavioral deficits. These results indicate that HMGB1/TLR2 activates an autocrine trophic signaling pathways in OLs and myelin to maintain structural and functional integrity of the white matter under ischemic conditions.
MeSH

DOI
10.1073/pnas.1702035114
PMID
28584116
Appears in Collections:
Journal Papers > School of Medicine / Graduate School of Medicine > Brain Science
Journal Papers > School of Medicine / Graduate School of Medicine > Neurology
Ajou Authors
김, 병곤  |  최, 월선  |  최, 준영
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