Histamine deficiency deteriorates LPS-induced periodontal diseases in a murine model via NLRP3/Caspase-1 pathway

Fujie Song; Xiyang Yang; Baoling Zhu; Yaoyang Xiong; Zhifeng Song; Xiangdong Yang; Yuanli Zheng

doi:10.1016/j.intimp.2022.109630

Histamine deficiency deteriorates LPS-induced periodontal diseases in a murine model via NLRP3/Caspase-1 pathway

Int Immunopharmacol. 2023 Feb:115:109630. doi: 10.1016/j.intimp.2022.109630. Epub 2022 Dec 24.

Authors

Fujie Song¹, Xiyang Yang², Baoling Zhu³, Yaoyang Xiong⁴, Zhifeng Song⁵, Xiangdong Yang⁶, Yuanli Zheng⁷

Affiliations

¹ Department of First Dental Clinic, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, College of Stomatology, Shanghai Jiao Tong University, National Center for Stomatology, National Clinical Research Center for Oral Diseases, Shanghai Key Laboratory of Stomatology, Shanghai 200011, China.
² Shanghai Institute of Cardiovascular Diseases, Zhongshan Hospital, Fudan University, Shanghai 200032, China.
³ Institutes of Biomedical Sciences, Fudan University, Shanghai 200032, China.
⁴ Department of Prosthodontics, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, College of Stomatology, Shanghai Jiao Tong University, National Center for Stomatology, National Clinical Research Center for Oral Diseases, Shanghai Key Laboratory of Stomatology, Shanghai 200011, China.
⁵ Department of oral mucosa and periodontal clinic, Shanghai Stomatological Hospital & School of Stomatology, Fudan University, Shanghai Key Laboratory of Craniomaxillofacial Development and Diseases, Fudan University, Shanghai 200433, China.
⁶ Shanghai Institute of Cardiovascular Diseases, Zhongshan Hospital, Fudan University, Shanghai 200032, China; Institutes of Biomedical Sciences, Fudan University, Shanghai 200032, China; Department of Cardiology, Third People's Hospital of Huizhou, Guangdong, 516003, China.. Electronic address: yangxiangdong_zs@163.com.
⁷ Department of First Dental Clinic, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, College of Stomatology, Shanghai Jiao Tong University, National Center for Stomatology, National Clinical Research Center for Oral Diseases, Shanghai Key Laboratory of Stomatology, Shanghai 200011, China. Electronic address: zhengyuanli2017@163.com.

PMID: 36571917
DOI: 10.1016/j.intimp.2022.109630

Abstract

Histamine is a versatile biogenic amine, generated by the unique enzyme histidine decarboxylase (Hdc). Accumulating evidence has proven that histamine plays important roles in numerous biological and pathophysiological processes. However, the role and mechanism of Hdc/Histamine signaling in periodontal diseases remain unclear. In our current study, the concentration of histamine increased in the serum, and Hdc gene expression was upregulated in the gingiva of WT mice with LPS-induced periodontal inflammation. With Hdc-GFP mice, we identified that Hdc/GFP in the periodontium was expressed in CD11b⁺ myeloid cells, rather than in tryptase-positive mast cells. Hdc-expressing CD11b⁺Gr-1⁺ neutrophils significantly increased in the peripheral blood of Hdc-GFP mice one day after LPS injection. Lack of histamine in Hdc^-/- mice not only promoted the activation and infiltration of more CD11b⁺ cells into the peripheral blood but also upregulated mRNA expression levels of IL-1β, IL-6, MCP-1and MMP9 in the gingiva compared to WT mice one day after LPS stimulation. 28 days after LPS treatment, we observed that Hdc^-/- mice exhibited more alveolar bone loss and more osteoclasts than WT mice, which was slightly ameliorated by the administration of exogenous histamine. In vivo and in vitro mechanistic studies revealed that the mRNA expression levels of proinflammatory cytokines and protein levels of NLRP3, Caspase-1, and cleaved-Caspase-1 were upregulated after blocking histamine receptor 1 and 2, especially histamine receptor 1. Taken together, CD11b⁺Gr-1⁺ neutrophils are the predominant Hdc-expressing sites in periodontal inflammation, and deficiency of endogenous histamine in Hdc^-/- mice exacerbates the destruction of the periodontium. Disruption of the histamine/H₁R/H₂R axis aggravates the inflammatory immune response via NLRP3/Casapse-1 pathway.

Keywords: Caspase-1; Histamine receptors; Histidine decarboxylase; Immune response.NLRP3; Inflammation; Neutrophil; Periodontitis.

MeSH terms

Animals
Caspase 1
Disease Models, Animal
Histamine* / metabolism
Inflammation / metabolism
Lipopolysaccharides / pharmacology
Mice
NLR Family, Pyrin Domain-Containing 3 Protein / genetics
Periodontal Diseases*
RNA, Messenger
Receptors, Histamine

Substances

Histamine
Lipopolysaccharides
NLR Family, Pyrin Domain-Containing 3 Protein
Caspase 1
Receptors, Histamine
RNA, Messenger
Nlrp3 protein, mouse