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Histamine acts via H4-receptor stimulation to cause augmented inflammation when lipopolysaccharide is co-administered with a nitrogen-containing bisphosphonate

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Abstract

Objective and methods

Nitrogen-containing bisphosphonates (NBPs, anti-bone-resorptive agents) have inflammatory side-effects. Alendronate (Ale, an NBP) intradermally injected into mouse ear-pinnae together with LPS (bacterial cell-wall component) induces augmented ear-swelling that depends on IL-1 and neutrophils. Using this model, we examined histamine’s involvement in Ale + LPS-induced inflammation.

Results

Ale increased histamine in ear-pinnae by inducing histidine decarboxylase (HDC). This induction was augmented by LPS. In HDC-deficient mice, such augmented ear-swelling was not induced. At peak-swelling, 74.5% of HDC-expressing cells were neutrophils and only 0.2% were mast cells (MCs). The augmented swelling was markedly reduced by a histamine H4-receptor (H4R) antagonist, but not by an H1R antagonist. In MC-deficient mice, unexpectedly, Ale + LPS induced prolonged ear-swelling that was augmented and more persistent than in normal mice. MCs highly expressed H4Rs and produced MCP-1(inflammatory cytokine that recruits macrophages) and IL-10 (anti-inflammatory cytokine) in response to an H4R agonist.

Conclusion

Histamine produced by HDC-induction mainly in infiltrated neutrophils stimulates H4Rs, leading to augmented Ale + LPS-induced ear-swelling via MCP-1 production by MCs. Since MCP-1 is produced by other cells, too, the contribution of MCs and their H4Rs to augmented ear-swelling is partial. In the later phase of the swelling, MCs may be anti-inflammatory via IL-10 production.

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Acknowledgements

The authors thank Dr. Robert Timms for his language-editing. We thank the Biomedical Research Core of Tohoku University Graduate School of Medicine for the use of its equipment. We thank Dr. Takashi Moriguchi and Dr. Jun Takai for providing HDC-GFP mice.

Funding

Research funding provided by Japan Society for Promotion of Science (18K17240, 21K10157 to KB).

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Authors and Affiliations

  1. Division of Orthodontics and Dentofacial Orthopedics, Graduate School of Dentistry, Tohoku University, 4-1 Seiryo-machi, Aoba-ku, 980-8575, Sendai, Japan

    Kanan Bando & Itaru Mizoguchi

  2. Department of Dento-Oral Anesthesiology, Graduate School of Dentistry, Tohoku University, 4-1 Seiryo-machi, Aoba-ku, 980-8575, Sendai, Japan

    Yukinori Tanaka

  3. Department of Oral and Maxillofacial Surgery, Graduate School of Dentistry, Tohoku University, 4-1 Seiryo-machi, Aoba-ku, 980-8575, Sendai, Japan

    Tetsu Takahashi & Yasuo Endo

  4. Division of Oral Immunology, Graduate School of Dentistry, Tohoku University, 4-1 Seiryo-machi, Aoba-ku, 980-8575, Sendai, Japan

    Shunji Sugawara

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  1. Kanan Bando
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  2. Yukinori Tanaka
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Study designed and conducted by KB, YE, YT, TT, IM, and SS. Data collected by KB. Data analyzed by KB and YE. Technically assisted by YT, YE, and SS. Manuscript written by KB and YE and approved by all authors.

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Correspondence to Kanan Bando.

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Bando, K., Tanaka, Y., Takahashi, T. et al. Histamine acts via H4-receptor stimulation to cause augmented inflammation when lipopolysaccharide is co-administered with a nitrogen-containing bisphosphonate. Inflamm. Res. 71, 1603–1617 (2022). https://doi.org/10.1007/s00011-022-01650-7

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