High Mobility Group Box 1 as an Autocrine Chemoattractant for Oligodendrocyte Lineage Cells in White Matter Stroke


 
 The migration of oligodendrocyte precursor cells (OPC) is a key process of remyelination, which is essential for the treatment of white matter stroke. This study aimed to investigate the role of HMGB1 (high mobility group box 1), a damage-associated molecular pattern released from dying oligodendrocytes, as an autocrine chemoattractant that promotes OPC migration.
 
 
 
 The migratory capacity of primary cultured OPCs was measured using the Boyden chamber assay. The downstream pathway of HMGB1-mediated OPC migration was specified by siRNA-induced knockdown or pharmacological blockade of TLR2 (toll-like receptor 2), RAGE (receptor for advanced glycation end product), Src, ERK1/2 (extracellular signal-regulated kinase1/2), and FAK (focal adhesion kinase). Conditioned media were collected from oxygen-glucose deprivation-treated oligodendrocytes, and the impact on OPC migration was assessed. Lesion size and number of intralesional Olig2(+) cells were analyzed in an in vivo model of white matter stroke with N5-(1-iminoethyl)-L-ornithine (L-NIO).
 
 
 
 HMGB1 treatment promoted OPC migration. HMGB1 antagonism reversed such effects to untreated levels. Among the candidates for the downstream signal of HMGB1-mediated migration, the knockdown of TLR2 rather than that of RAGE attenuated the migration-promoting effect of HMGB1. Further specification of the HMGB1-TLR2 axis revealed that the phosphorylation of ERK1/2 and its downstream molecule FAK, rather than of Src, was decreased in TLR2-knockdown OPCs, and pharmacological inhibition of ERK1/2 and FAK led to decreased OPC migration. Oxygen-glucose deprivation-conditioned media promoted OPC migration, suggesting the autocrine chemoattractant function of HMGB1. In vivo, TLR2(−/−)-mice showed lesser intralesional Olig2(+) cells compared to wild-type controls in response to L-NIO induced ischemic injury regardless of HMGB1 administration.
 
 
 
 HMGB1, through the TLR2-ERK1/2-FAK axis, functions as an autocrine chemoattractant to promote OPC migration, which is an initial and indispensable step in remyelination. Thus, a novel treatment strategy for white matter stroke based on the HMGB1-TLR2 axis in the oligodendrocyte lineage could be feasible.
