Indoleamine 2,3-dioxygenase mediates the therapeutic effects of adipose-derived stromal/stem cells in experimental periodontitis by modulating macrophages through the kynurenine-AhR-NRF2 pathway

Hanyue Li; Yu Yuan; Hongying Chen; Hongwei Dai; Jie Li

doi:10.1016/j.molmet.2022.101617

Indoleamine 2,3-dioxygenase mediates the therapeutic effects of adipose-derived stromal/stem cells in experimental periodontitis by modulating macrophages through the kynurenine-AhR-NRF2 pathway

Mol Metab. 2022 Dec:66:101617. doi: 10.1016/j.molmet.2022.101617. Epub 2022 Oct 18.

Authors

Hanyue Li¹, Yu Yuan¹, Hongying Chen¹, Hongwei Dai², Jie Li³

Affiliations

¹ College of Stomatology, Chongqing Medical University, Chongqing, 401147, China; Chongqing Key Laboratory of Oral Diseases and Biomedical Sciences, Chongqing Medical University, Chongqing, 401147, China; Chongqing Municipal Key Laboratory of Oral Biomedical Engineering of Higher Education, Chongqing Medical University, Chongqing, 401147, China.
² College of Stomatology, Chongqing Medical University, Chongqing, 401147, China; Chongqing Key Laboratory of Oral Diseases and Biomedical Sciences, Chongqing Medical University, Chongqing, 401147, China; Chongqing Municipal Key Laboratory of Oral Biomedical Engineering of Higher Education, Chongqing Medical University, Chongqing, 401147, China. Electronic address: dai64@hospital.cqmu.edu.cn.
³ College of Stomatology, Chongqing Medical University, Chongqing, 401147, China; Chongqing Key Laboratory of Oral Diseases and Biomedical Sciences, Chongqing Medical University, Chongqing, 401147, China; Chongqing Municipal Key Laboratory of Oral Biomedical Engineering of Higher Education, Chongqing Medical University, Chongqing, 401147, China. Electronic address: jieli@hospital.cqmu.edu.cn.

Abstract

Objectives: Mesenchymal stromal/stem cell (MSC)-based therapy has become a promising approach to periodontal tissue repair. Adipose-derived stromal/stem cells (ASCs), compared with other dental or non-dental MSCs, serve as promising candidates for MSC therapy due to non-invasive acquisition and abundant sources. This study aimed to explore the effects of ASC therapy in experimental periodontitis and the underlying mechanism.

Methods: Micro-CT was performed to evaluate the alveolar bone parameters following local injection of ASCs. Immunohistochemistry and immunofluorescence were employed to detect the expression of IL-1β, osteocalcin (OCN), nuclear factor (erythroid-derived 2)-like 2 (NRF2), and surface markers of macrophage polarization. Afterward, multiple reaction monitoring (MRM)-based targeted tryptophan metabolomic analysis was used to examine the ASC metabolites. Chromatin immunoprecipitation (ChIP)-qPCR assay was performed to investigate the direct binding of aryl hydrocarbon receptor (AhR) and NRF2.

Results: Alveolar bone loss was reduced, and the ratio of iNOS⁺/CD206⁺ macrophages was significantly decreased after ASC injection in the rat models of periodontitis. ASCs promoted NRF2 expression and activation in macrophages, while NRF2 silencing in macrophages blocked the regulation of ASCs on macrophages. Furthermore, the expression of indoleamine 2,3-dioxygenase (IDO) of ASCs in the inflammatory condition was high. The inhibitor of IDO, 1-methyltryptophan (1-MT), impaired the therapeutic effects of ASCs in experimental periodontitis and regulation of macrophage polarization. Mechanistically, kynurenine (Kyn), a metabolite of ASCs catalyzed by IDO, activated AhR and enhanced its binding to the promoter of NRF2, which stimulated M2 macrophage polarization.

Conclusions: These findings suggested that ASCs can alleviate ligature-induced periodontitis through modulating macrophage polarization by the IDO-dependent Kyn-AhR-NRF2 pathway, uncovering a novel mechanism and providing a scientific basis for ASC-based therapy in experimental periodontitis.

Keywords: Adipose-derived stromal/stem cells (ASCs); Experimental periodontitis; Indoleamine 2,3-dioxygenase (IDO); Macrophages; Therapy.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Indoleamine-Pyrrole 2,3,-Dioxygenase / metabolism
Kynurenine / metabolism
Macrophages / metabolism
Mesenchymal Stem Cells* / metabolism
NF-E2-Related Factor 2
Periodontitis* / therapy
Rats
Receptors, Aryl Hydrocarbon / metabolism

Substances

Kynurenine
Receptors, Aryl Hydrocarbon
Indoleamine-Pyrrole 2,3,-Dioxygenase
NF-E2-Related Factor 2