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Histamine Induces Upregulated Expression of Histamine Receptors and Increases Release of Inflammatory Mediators from Microglia

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Abstract

Histamine is a potent mediator of inflammation and a regulator of innate and adaptive immune responses. However, the influence of histamine on microglia, the resident immune cells in the brain, remains uninvestigated. In the present study, we found that microglia can constitutively express all four histamine receptors (H1R, H2R, H3R, and H4R), and the expression of H1R and H4R can be selectively upregulated in primary cultured microglia in a dose-dependent manner by histamine. Histamine can also dose-dependently stimulate microglia activation and subsequently production of proinflammatory factors tumor necrosis factor (TNF)-alpha and interleukin-6 (IL-6). The antagonists of H1R and H4R but not H2R and H3R reduced histamine-induced TNF-alpha and IL-6 production, MAPK and PI3K/AKT pathway activation, and mitochondrial membrane potential loss in microglia, suggesting that the actions of histamine are via H1R and H4R. On the other hand, inhibitors of JNK, p38, or PI3K suppressed histamine-induced TNF-alpha and IL-6 release from microglia. Histamine also activated NF-kappa B and ammonium pyrrolidinedithiocarbamate, an inhibitor of NF-kappa B, and reduced histamine-induced TNF-alpha and IL-6 release. In summary, the present study identifies the expression of histamine receptors on microglia. We also demonstrate that histamine induced TNF-alpha and IL-6 release from activated microglia via H1R and H4R-MAPK and PI3K/AKT-NF-kappa B signaling pathway, which will deepen the understanding of microglia-mediated neuroinflammatory symptoms of chronic neurodegenerative disease.

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Acknowledgment

This project was sponsored by the grants from the National Natural Science Foundation of China (no. 81102422, 81373398), the Natural Science Foundation of Jiangsu Province (BK2010020), and a Project Funded by the Priority Academic Program Development of Jiangsu Higher Education Institutions (PAPD).

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The authors declare that this article content has no conflicts of interest.

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Authors and Affiliations

  1. Clinical Research Center, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu, 210029, China

    Hongquan Dong, Wei Zhang, Xiaoning Zeng, Huiwen Zhang, Shaoheng He & Shu Zhang

  2. Department of Anesthesiology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, People’s Republic of China

    Hongquan Dong

  3. Department of Pharmacology, Jiangsu Key Laboratory of Neurodegeneration, Nanjing Medical University, Nanjing, People’s Republic of China

    Gang Hu

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  1. Hongquan Dong
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  2. Wei Zhang
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  4. Gang Hu
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Correspondence to Shaoheng He or Shu Zhang.

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Hongquan Dong and Wei Zhang contributed equally to this work.

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Dong, H., Zhang, W., Zeng, X. et al. Histamine Induces Upregulated Expression of Histamine Receptors and Increases Release of Inflammatory Mediators from Microglia. Mol Neurobiol 49, 1487–1500 (2014). https://doi.org/10.1007/s12035-014-8697-6

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  • DOI: https://doi.org/10.1007/s12035-014-8697-6

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