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Histamine Induces Microglia Activation and the Release of Proinflammatory Mediators in Rat Brain Via H1R or H4R

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Abstract

Histamine is a major peripheral inflammatory mediator and a neurotransmitter in the central nervous system. We have reported that histamine induces microglia activation and releases proinflammatory factors in primary cultured microglia. Whether histamine has similar effects in vivo is unknown. In the present study, we aimed to investigate the role of histamine and its receptors in the release of inflammatory mediators and activation of microglia in rat brain. We site-directed injected histamine, histamine receptor agonists or histamine receptor antagonists in the rat lateral ventricle using stereotaxic techniques. Flow cytometry was employed to determine histamine receptor expression in rat microglia. Microglia activation was assessed by Iba1 immunohistochemistry. The levels of tumour necrosis factor-alpha (TNF-α), interleukin-1beta (IL-1β) and interleukin-10 (IL-10) were measured with commercial enzyme-linked immunosorbent assay (ELISA) kits, TNF-α, IL-1β and IL-10 mRNA expressions were determined with Quantitative Real-Time Polymerase Chain Reaction (qRT-PCR). We found that all four types of histamine receptors were expressed in rat brain microglia. Histamine was able to induce microglia activation and subsequent production of the inflammatory factors TNF-α, IL-1β and IL-10, and these effects were partially abolished by H1R and H4R antagonists. However, H2R and H3R antagonists significantly increased production of TNF-α and IL-1β, and decreased IL-10 levels. The H1R or H4R agonists stimulated the production of TNF-α and IL-1β, while the H2R or H3R agonists increased IL-10 release. Our results demonstrate that histamine induces microglia activation and the release of both proinflammatory and anti-inflammatory factors in rat brain, thus contributing to the development of inflammation in the brain.

Histamine induces microglia activation and the release of both proinflammatory (TNF-α and IL-1β) and anti-inflammatory factors (IL-10) in rat brain, thus contributing to the development of inflammation in the brain.

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Acknowledgements

This project was sponsored by the National Natural Science Foundation of China (No. 81102422, 81373398, 81570522 and 81501202), Hubei natural science foundation (2018CFB301), but they had no role in the design of the study collection, analysis, or interpretation of the data; or writing of the manuscript. We would like to thank the Core Facility of Jiangsu Provincial People’s Hospital for its help in the detection of experimental samples.

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  1. Wei Zhang, Xiaojun Zhang and Yan Zhang contributed equally to this work.

Authors and Affiliations

  1. Department of Laboratory Medicine, the First Affiliated Hospital of Nanjing Medical University, Nanjing, People’s Republic of China

    Wei Zhang

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

    Xiaojun Zhang

  3. Department of Anesthesiology, Wuhan Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei Province, China

    Yan Zhang

  4. Department of Geriatrics, the Second Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu, 210029, People’s Republic of China

    Chen Qu

  5. Department of Gastroenterology, the First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu, 210029, People’s Republic of China

    Xiqiao Zhou

  6. Clinical Research Center, the First Affiliated Hospital of Nanjing Medical University, 300 Guangzhou Road, Nanjing, Jiangsu, 210029, People’s Republic of China

    Shu Zhang

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All experiments were carried out according to the National Institutes of Health Guide for the Care and Use of Laboratory Animals (publication no. 85–23, revised 1985) and the Guidelines for the Care and Use of Animals in Neuroscience Research by the Society for Neuroscience and approved by IACUC (Institutional Animal Care and Use Committee of Nanjing Medical University, NO: 14030126).

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Zhang, W., Zhang, X., Zhang, Y. et al. Histamine Induces Microglia Activation and the Release of Proinflammatory Mediators in Rat Brain Via H1R or H4R. J Neuroimmune Pharmacol 15, 280–291 (2020). https://doi.org/10.1007/s11481-019-09887-6

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