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

• Published in: Proceedings of the National Academy of Sciences - PNAS Vol. 114; no. 25; pp. E4987 - E4995
• Main Authors: Choi, Jun Young, 최준영, Cui, Yuexian, 최월선, Chowdhury, Samma Tasneem, Kim, Byung Gon, 김병곤
• Format: Journal Article
• Language: English
• Published: United States National Academy of Sciences 20.06.2017
• Series: PNAS Plus
• Subjects: Animals; Autocrine signalling; Biological Sciences; Brain; Brain Ischemia - metabolism; Cell culture; Cells, Cultured; Coinjection; Conditioning; Death; Degeneration; Demyelinating Diseases - metabolism; Demyelination; Deprivation; Endothelin 1; Endothelin-1 - metabolism; Endothelins; Glucose; Glycyrrhizin; HMGB1 protein; HMGB1 Protein - metabolism; Integrity; Ischemia; Ligands; Male; Mice; Mice, Inbred C57BL; Mobility; Mortality; Myelin; Myelin Sheath - metabolism; Oligodendrocytes; Oligodendroglia - metabolism; Oxygen; PNAS Plus; Sensorimotor system; Signal transduction; Signal Transduction - physiology; Stroke; Stroke - metabolism; Structure-function relationships; Substantia alba; TLR2 protein; Toll-Like Receptor 2 - metabolism; Toll-like receptors; Translocation; White Matter - metabolism; myelination; white matter stroke; HMGB1; oligodendrocyte; toll-like receptor 2
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.1702035114

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.