• Kazue Hisaoka-Nakashima, Yuka Takeuchi, Yukino Saito, Takahisa Shimoda, Yoki Nakamura, Dengli Wang, Keyue Liu, Masahiro Nishibori, and Norimitsu Morioka.
• Department of Pharmacology, Graduate School of Biomedical & Health Sciences, Hiroshima University, Kasumi 1-2-3, Minami-ku, Hiroshima, Japan.
• Neuroscience. 2024 Nov 12; 560: 566656-66.

AbstractStress, a risk factor for major depressive disorder and Alzheimer disease, leads to the release of high-mobility group box-1 (HMGB1) protein, which in turn causes neuroinflammation. The mechanism underlying stress-induced HMGB1 release is unknown, but stress-associated glucocorticoids could be involved. Primary cultured rat cortical microglia and neurons were treated with corticosterone, a stress-associated glucocorticoid, and HMGB1 release was measured by ELISA and western blotting to test this hypothesis. With corticosterone treatment, significant HMGB1 was released in microglia but not in neuronal cell cultures. HMGB1 mRNA expression and HMGB1 protein expression in microglia were not affected by corticosterone treatment. Thus, the source of extracellular HMGB1 released into the medium is likely to be existing nuclear HMGB1 rather than newly synthesized HMGB1. Corticosterone-induced HMGB1 release in microglia culture was significantly attenuated by blocking glucocorticoid receptors but not mineralocorticoid receptors. Dexamethasone, a selective glucocorticoid receptor agonist, and dexamethasone-bovine serum albumin (BSA), a membrane-impermeable glucocorticoid receptor agonist used to confirm the membrane receptor-mediated effects of glucocorticoids, increased the release of HMGB1. Immunocytochemistry showed that HMGB1 translocated from the nucleus to the cytoplasm following dexamethasone or dexamethasone-BSA treatment through glucocorticoid receptors. The present findings suggest that glucocorticoids stimulate microglial membrane glucocorticoid receptors and trigger cytoplasmic translocation and extracellular release of nuclear HMGB1. Thus, under stress conditions, glucocorticoids induce microglial HMGB1 release, leading to a neuroinflammatory state that could mediate neurological disorders.Copyright © 2024 International Brain Research Organization (IBRO). Published by Elsevier Inc. All rights reserved.

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