Hannah Aucott1, Johan Lundberg2,3, Henna Salo1, Lena Klevenvall4, Peter Damberg2, Lars Ottosson4, Ulf Andersson4, Staffan Holmin2,3, Helena Erlandsson Harris1. 1. Department of Medicine Solna, Rheumatology Unit, Centre for Molecular Medicine, Karolinska Institutet, Stockholm, Sweden. 2. Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden. 3. Department of Neuroradiology, Karolinska University Hospital, Stockholm, Sweden. 4. Department of Women's and Children's Health, Karolinska Institutet, Stockholm, Sweden.
Abstract
BACKGROUND: Neuroinflammation triggered by infection or trauma is the cause of central nervous system dysfunction. High-mobility group box 1 protein (HMGB1), released from stressed and dying brain cells, is a potent neuroinflammatory mediator. The proinflammatory functions of HMGB1 are tightly regulated by post-translational redox modifications, and we here investigated detailed neuroinflammatory responses induced by the individual redox isoforms. METHODS: Male Dark Agouti rats received a stereotactic injection of saline, lipopolysaccharide, disulfide HMGB1, or fully reduced HMGB1, and were accessed for blood-brain barrier modifications using magnetic resonance imaging (MRI) and inflammatory responses by immunohistochemistry. RESULTS AND CONCLUSIONS: Significant blood-brain barrier disruption appeared 24 h after injection of lipopolysaccharide, disulfide HMGB1, or fully reduced HMGB1 compared to controls, as assessed in post-gadolinium T1-weighted MRI images and confirmed by increased uptake of FITC-conjugated dextran. Immunohistochemistry revealed that both HMGB1 isoforms also induced a local production of IL-1β. Additionally, disulfide HMGB1 increased major histocompatibility complex class II expression and apoptosis. Together, the results demonstrate that extracellular, cerebral HMGB1 causes significant blood-brain barrier disruption in a redox-independent manner and activates several components of neuroinflammation. Blocking HMGB1 might potentially improve clinical outcome in conditions such as stroke and traumatic brain injury. The Author(s). Published by S. Karger AG, Basel.
BACKGROUND: Neuroinflammation triggered by infection or trauma is the cause of central nervous system dysfunction. High-mobility group box 1 protein (HMGB1), released from stressed and dying brain cells, is a potent neuroinflammatory mediator. The proinflammatory functions of HMGB1 are tightly regulated by post-translational redox modifications, and we here investigated detailed neuroinflammatory responses induced by the individual redox isoforms. METHODS: Male Dark Agouti rats received a stereotactic injection of saline, lipopolysaccharide, disulfideHMGB1, or fully reduced HMGB1, and were accessed for blood-brain barrier modifications using magnetic resonance imaging (MRI) and inflammatory responses by immunohistochemistry. RESULTS AND CONCLUSIONS: Significant blood-brain barrier disruption appeared 24 h after injection of lipopolysaccharide, disulfideHMGB1, or fully reduced HMGB1 compared to controls, as assessed in post-gadolinium T1-weighted MRI images and confirmed by increased uptake of FITC-conjugated dextran. Immunohistochemistry revealed that both HMGB1 isoforms also induced a local production of IL-1β. Additionally, disulfideHMGB1 increased major histocompatibility complex class II expression and apoptosis. Together, the results demonstrate that extracellular, cerebral HMGB1 causes significant blood-brain barrier disruption in a redox-independent manner and activates several components of neuroinflammation. Blocking HMGB1 might potentially improve clinical outcome in conditions such as stroke and traumatic brain injury. The Author(s). Published by S. Karger AG, Basel.
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