Nlrp3 inflammasome drives regulatory T cell depletion to accelerate periapical bone erosion

Konghuai Wang; Jiayi Liu; Junli Yue; Lu Zhou; Hanqing Mao; Jiaqi Li; Zhijun Sun; Zhi Chen; Lu Zhang

doi:10.1111/iej.14062

Nlrp3 inflammasome drives regulatory T cell depletion to accelerate periapical bone erosion

Int Endod J. 2024 Mar 5. doi: 10.1111/iej.14062. Online ahead of print.

Authors

Konghuai Wang¹, Jiayi Liu¹, Junli Yue^{1

2}, Lu Zhou¹, Hanqing Mao¹, Jiaqi Li¹, Zhijun Sun^{1

3}, Zhi Chen^{1

2}, Lu Zhang^{1

2}

Affiliations

¹ State Key Laboratory of Oral & Maxillofacial Reconstruction and Regeneration, Key Laboratory of Oral Biomedicine Ministry of Education, Hubei Key Laboratory of Stomatology, School & Hospital of Stomatology, Wuhan University, Wuhan, China.
² Department of Endodontics, School and Hospital of Stomatology, Wuhan University, Wuhan, China.
³ Department of Oral Maxillofacial-Head Neck Oncology, School and Hospital of Stomatology, Wuhan University, Wuhan, China.

PMID: 38441141
DOI: 10.1111/iej.14062

Abstract

Aim: Apical periodontitis is an inflammatory disorder triggered by an immune response to bacterial infection, leading to the periapical tissue damage and alveolar resorption. However, the underlying mechanisms driving this process remain elusive, due to the complex and interconnected immune microenvironment within the local lesion site. In this study, the influence of Nlrp3 inflammasome-mediated immune response on the apical periodontitis was investigated.

Methodology: RNA sequencing, immunohistochemistry and ELISA assay were performed to investigate the activation of Nlrp3 inflammasome signalling pathways in the human periapical tissues, including radicular cysts, periapical granulomas and healthy oral mucosa. A mouse model of apical periodontitis was established to study the role of Nlrp3 knockout in periapical bone resorption and Treg cell stability, and the underlying mechanism was explored through in vitro experiments. In vivo Treg cell adoptive transfer was performed to investigate the effects of Treg cells on the progression of apical periodontitis.

Results: Our findings find that the hyperactivated Nlrp3 inflammasome is present in human periapical lesions and plays a vital role in the immune-related periapical bone loss. Using a mouse model of apical periodontitis, we observe that Nlrp3 deficiency is resistant to bone resorption. This protection was accompanied by elevated generation and infiltration of local Treg cells that displayed a notable ability to suppress RANKL-dependent osteoclast differentiation. In terms of the mechanism of action, Nlrp3 deficiency directly inhibits the osteoclast differentiation and bone loss through JNK/MAPK and NF-κB pathways. In addition, Nlrp3 induces pyroptosis in the stem cells from apical papilla (SCAPs), and the subsequent release of cytokines affects the stability of Treg cell in periapical lesions, leading indirectly to enhanced bone resorption. In turn, adoptive transfer of both Nlrp3-deficient and wild-type Treg cells effectively prevent the bone erosion during apical periodontitis.

Conclusions: Together, our data identify that the Nlrp3 inflammasome modulates the Treg cell stability and osteoclastogenesis in the periapical inflammatory microenvironment, thus determining the progression of bone erosion.

Keywords: cytokines; immunity; inflammasome; osteoclasts; pyroptosis; signal transduction.

Abstract

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