Abstract
BackgroundMounting evidence has indicated that high-mobility group box 1 (HMGB1) is involved in cell activation and migration. Our previous study demonstrated that methamphetamine mediates activation of astrocytes via sigma-1 receptor (σ-1R). However, the elements downstream of σ-1R in this process remain poorly understood. Thus, we examined the molecular mechanisms involved in astrocyte activation and migration induced by methamphetamine.MethodsThe expression of HMGB1, σ-1R, and glial fibrillary acidic protein (GFAP) was examined by western blot and immunofluorescent staining. The phosphorylation of cell signaling pathways was detected by western blot, and cell migration was examined using a wound-healing assay in rat C6 astroglia-like cells transfected with lentivirus containing red fluorescent protein (LV-RFP) as well as in primary human astrocytes. The role of HMGB1 in astrocyte activation and migration was validated using a siRNA approach.ResultsExposure of C6 cells to methamphetamine increased the expression of HMGB1 via the activation of σ-1R, Src, ERK mitogen-activated protein kinase, and downstream NF-κB p65 pathways. Moreover, methamphetamine treatment resulted in increased cell activation and migration in C6 cells and primary human astrocytes. Knockdown of HMGB1 in astrocytes transfected with HMGB1 siRNA attenuated the increased cell activation and migration induced by methamphetamine, thereby implicating the role of HMGB1 in the activation and migration of C6 cells and primary human astrocytes.ConclusionsThis study demonstrated that methamphetamine-mediated activation and migration of astrocytes involved HMGB1 up-regulation through an autocrine mechanism. Targeting HMGB1 could provide insights into the development of a potential therapeutic approach for alleviation of cell activation and migration of astrocytes induced by methamphetamine.
Highlights
Mounting evidence has indicated that high-mobility group box 1 (HMGB1) is involved in cell activation and migration
Methamphetamine mediates the expression of HMGB1 in astrocytes Because reactive astrocytes undergo rapid proliferation [8, 12, 13], we first investigated the effect of methamphetamine on cell proliferation in C6 cells
G, methamphetamine treatment increased the expression of glial fibrillary acidic protein (GFAP), which was attenuated by transfection with siRNA HMGB1. These findings clearly demonstrated that HMGB1 is involved in the activation of astrocytes induced by methamphetamine
Summary
Mounting evidence has indicated that high-mobility group box 1 (HMGB1) is involved in cell activation and migration. Our previous study demonstrated that methamphetamine mediates activation of astrocytes via sigma-1 receptor (σ-1R). We examined the molecular mechanisms involved in astrocyte activation and migration induced by methamphetamine. Zhang et al Journal of Neuroinflammation (2015) 12:156 in regulating and maintaining CNS homeostasis [5, 6]. In addition to their normal physiological functions, astrocytes can be pathologically activated, and they are characterized by abnormal morphology with reactive astrogliosis [7,8,9,10,11]. Our previous study demonstrated that methamphetamine-mediated activation of astrocytes involves the up-regulation of σ-1R through a positive feedback mechanism.
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