Histamine upregulates the expression of histamine receptors and increases the neuroprotective effect of astrocytes

Jiawen Xu,Xiang Zhang,Wenjie Jin,Nana Li,Yiwei Wang,Yanning Qian,Qingqing Qian,Hongquan Dong

doi:10.1186/s12974-018-1068-x

Abstract

BackgroundAstrocytes have attracted increasing attention over recent decades for their role in neuroinflammation. Histamine, a major aminergic brain neurotransmitter, has an important influence on the main activities of astrocytes, such as ion homeostasis, energy metabolism, and neurotransmitter clearance. However, little is known about the impact of histamine on astrocyte immunomodulatory function.MethodsThe expression of all known histamine receptor subtypes was examined in primary astrocytes. Then, primary astrocytes were pretreated with selective histamine receptor antagonists and stimulated with histamine. Cellular activation, proinflammatory cytokine production, and expression of neurotrophic factors were assessed.ResultsAstrocytes could constitutively express three histamine receptors (H1R, H2R, and H3R), and these three histamine receptors could be selectively upregulated to varying degrees upon histamine treatment. Histamine also dose-dependently stimulated astrocyte activation and subsequent production of glial cell-derived neurotrophic factor (GDNF), whereas it suppressed the secretion of the proinflammatory factors tumor necrosis factor-alpha (TNF-α) and interleukin-1β (IL-1β). The effects of histamine were completely abolished by either an H1R or H3R antagonist, while an H2R antagonist attenuated the effects partly.ConclusionsThe present study identified the expression of H1R, H2R, and H3R on astrocytes. We also demonstrated that negative regulation of astrocytic TNF-α and IL-1β production and the enhancement of astrocytic GDNF stimulated by histamine were receptor-mediated processes in which all three of the expressed histamine receptors (H1R, H2R, and H3R) were involved. These findings may further clarify the involvement and mechanism of astrocyte activation in neuroinflammation.

Highlights

Astrocytes have attracted increasing attention over recent decades for their role in neuroinflammation
Selective expression of histamine receptors H1R, H2R, and H3R but not H4R in primary astrocytes Numerous studies have demonstrated that cultured astrocytes from different mammalian brain regions express H1 and H2 receptors to varying degrees [18,19,20,21]
By triggering H1, H2, and H3 receptors, histamine suppressed the production of TNF-α and IL-1β and stimulated the synthesis of glial cell-derived neurotrophic factor (GDNF) by astrocytes

Summary

Introduction

Astrocytes have attracted increasing attention over recent decades for their role in neuroinflammation. Strong activation of astrocytes leads to the secretion of large amounts of cytokines, chemokines, reactive oxygen species, and proinflammatory mediators, affecting the cellular state of surrounding cells such as microglia, neurons, and astrocytes themselves, leading to excitotoxicity, neurodegeneration, and apoptosis [8]. Thanks to their multifaceted role in the inflamed CNS, astrocytes are well suited to determine the site, size, and character of the immune response [9]. In this sense, understanding the regulators and related mechanisms involved in astrocyte activation is key in eliminating deleterious effects of this cell population

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