Corticosterone Induces HMGB1 Release in Primary Cultured Rat Cortical Astrocytes: Involvement of Pannexin-1 and P2X7 Receptor-Dependent Mechanisms.

Kazue Hisaoka-Nakashima,Masahiro Nishibori,Keyue Liu,Dengli Wang,Yoki Nakamura,Honami Azuma,Yoshihiro Nakata,Norimitsu Morioka,Fumina Ishikawa,Hidenori Wake

doi:10.3390/cells9051068

Kazue Hisaoka-Nakashima, Masahiro Nishibori + Show 8 more

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https://doi.org/10.3390/cells9051068

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Journal: Cells	Publication Date: Apr 25, 2020
Citations: 21	License type: CC BY 4.0

Affiliation: Hiroshima University, Okayama University

Abstract

A major risk factor for major depressive disorder (MDD) is stress. Stress leads to the release of high-mobility group box-1 (HMGB1), which in turn leads to neuroinflammation, a potential pathophysiological basis of MDD. The mechanism underlying stress-induced HMGB1 release is not known, but stress-associated glucocorticoids could be involved. To test this, rat primary cultured cortical astrocytes, the most abundant cell type in the central nervous system (CNS), were treated with corticosterone and HMGB1 release was assessed by Western blotting and ELISA. Significant HMGB1 was released with treatment with either corticosterone or dexamethasone, a synthetic glucocorticoid. HMGB1 translocated from the nucleus to the cytoplasm following corticosterone treatment. HMGB1 release was significantly attenuated with glucocorticoid receptor blocking. In addition, inhibition of pannexin-1, and P2X7 receptors led to a significant decrease in corticosterone-induced HMGB1 release. Taken together, corticosterone stimulates astrocytic glucocorticoid receptors and triggers cytoplasmic translocation and extracellular release of nuclear HMGB1 through a mechanism involving pannexin-1 and P2X7 receptors. Thus, under conditions of stress, glucocorticoids induce astrocytic HMGB1 release, leading to a neuroinflammatory state that could mediate neurological disorders such as MDD.

Highlights

Major depressive disorder (MDD) is one of the most widespread, debilitating mental illnesses, affecting more than 300 million people worldwide [1]
The current study demonstrated that corticosterone, a major stress hormone in rodents, directly stimulates astrocytes through the glucocorticoid receptor and triggers cytoplasmic translocation and extracellular release of nuclear high-mobility group box-1 (HMGB1)
Once released into the extracellular space, HMGB1 is found in a number of processes including inflammation through its receptors such as toll-like receptor 4 (TLR4) and receptor for advanced glycation end-products (RAGE) [45,46]

Summary

Introduction

Major depressive disorder (MDD) is one of the most widespread, debilitating mental illnesses, affecting more than 300 million people worldwide [1]. Stress is a major risk factor for psychiatric disorders including MDD [2]. Neuroinflammatory processes, of both the peripheral and central innate immune systems, are evoked by stress [3,4]. Efforts have been made to identify key mediators of stress-induced inflammation in the context of MDD. Cellular and psychological stress initiates the release of endogenous factors known as danger- or damage-associated molecular patterns (DAMPs) from immune and non-immune. HMGB1 is a major regulator of innate immunity and, in response to stress, can induce sterile inflammation as a DAMP [11]

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