IL-1 receptor antagonist (IL-1RA) suppresses a hyper-IL-17 response-mediated bone loss in a murine experimental periodontitis

Jinmei Zhang; Angela X Wang; Yafei Wu; Shaoping Zhang

doi:10.1016/j.archoralbio.2022.105555

IL-1 receptor antagonist (IL-1RA) suppresses a hyper-IL-17 response-mediated bone loss in a murine experimental periodontitis

Arch Oral Biol. 2022 Dec:144:105555. doi: 10.1016/j.archoralbio.2022.105555. Epub 2022 Sep 27.

Authors

Jinmei Zhang¹, Angela X Wang², Yafei Wu³, Shaoping Zhang⁴

Affiliations

¹ Department of Periodontics, College of Dentistry, University of Iowa, Iowa City, IA, USA; State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, China.
² Department of Periodontics, College of Dentistry, University of Iowa, Iowa City, IA, USA.
³ State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, China.
⁴ Department of Periodontics, College of Dentistry, University of Iowa, Iowa City, IA, USA. Electronic address: shaoping-zhang@uiowa.edu.

PMID: 36191445
DOI: 10.1016/j.archoralbio.2022.105555

Abstract

Objective: We aimed to assess the role of interleukin - 1 receptor antagonist (IL-1RA) in a ligature-induced periodontal (LIP) model and the mechanism of IL-1RA in regulating the IL-17-mediated periodontal bone loss.

Design: Periodontal bone loss was induced through the LIP model in WT and Il1ra^-/- mice and measured by micro(μ) CT. Transcription of upstream IL-17 production signals and downstream targets in the ligated gingiva was compared by the real-time quantitative PCR (RT-qPCR) between WT and Il1ra^-/- mice. Single-cell suspensions were prepared in gingiva and cervical lymph nodes and were analyzed by fluorescence-activated cell sorting to quantify IL-17⁺ cells and IL-17-secreting subpopulations. We locally delivered an anti-IL-17 neutralizing antibody to the ligated gingiva and compared the bone loss with the isotype control antibody-treated Il1ra^-/- mice.

Results: Il1ra^-/- mice manifested significantly more bone loss than that of WT mice in the LIP model. Il17 and IL-17-associated transcripts (Il1b, Il6, Il23, Tgfb), Inos, Mrc1, Mmp13, and Rank were upregulated in the gingiva of Il1ra^-/- mice in comparison to WT mice. Significantly more IL-17⁺ immune cells (CD45⁺IL17⁺) are present in the gingiva of Il1ra^-/- mice with the majority of being TCR γδ T cells (CD45⁺IL-17⁺CD3⁺TCR γδ⁺) than WT mice^. The anti-IL-17 neutralizing antibody treatment attenuated the alveolar bone loss in the LIP model.

Conclusion: IL-1RA plays a protective role in the murine LIP model by suppressing an expansion of the IL-17⁺ cells and preventing a hyper-IL-17 response in the gingiva.

Keywords: Interleukin-1 receptor antagonist; Interleukin-17; Periodontitis; TCR γδ T cells.

MeSH terms

Alveolar Bone Loss* / pathology
Alveolar Bone Loss* / prevention & control
Animals
Antibodies, Neutralizing / pharmacology
Bone Diseases, Metabolic*
Interleukin 1 Receptor Antagonist Protein / pharmacology
Mice
Periodontitis* / drug therapy
Periodontitis* / pathology
Receptors, Antigen, T-Cell
Receptors, Interleukin-1
Th17 Cells

Substances

Antibodies, Neutralizing
Interleukin 1 Receptor Antagonist Protein
Receptors, Antigen, T-Cell
Receptors, Interleukin-1