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High Mobility Group Box 1 as an Autocrine Chemoattractant for Oligodendrocyte Lineage Cells in White Matter Stroke.
Choi, Jun Young; Jin, Xuelian; Kim, Hanki; Koh, Seungyon; Cho, Hyo Jin; Kim, Byung Gon.
Afiliação
  • Choi JY; Department of Brain science, Ajou University School of Medicine, Republic of Korea (J.Y.C., X.J., H.K., S.K., H.J.C., B.G.K.).
  • Jin X; Department of Neurology, Ajou University School of Medicine, Republic of Korea (J.Y.C., S.K., B.G.K.).
  • Kim H; Department of Brain science, Ajou University School of Medicine, Republic of Korea (J.Y.C., X.J., H.K., S.K., H.J.C., B.G.K.).
  • Koh S; Neuroscience graduate program, Ajou University Graduate School of Medicine, Republic of Korea (X.J., H.K., S.K.).
  • Cho HJ; Department of Nephrology, Suqian First Hospital, Jiangsu, China (X.J.).
  • Kim BG; Department of Brain science, Ajou University School of Medicine, Republic of Korea (J.Y.C., X.J., H.K., S.K., H.J.C., B.G.K.).
Stroke ; 54(2): 575-586, 2023 Feb.
Article em En | MEDLINE | ID: mdl-36490365
BACKGROUND: 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. METHODS: 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). RESULTS: 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. CONCLUSIONS: 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.
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Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Acidente Vascular Cerebral / Proteína HMGB1 / Substância Branca Limite: Animals Idioma: En Ano de publicação: 2023 Tipo de documento: Article

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Acidente Vascular Cerebral / Proteína HMGB1 / Substância Branca Limite: Animals Idioma: En Ano de publicação: 2023 Tipo de documento: Article