"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"
作者全名："Li, Hanyue; Yuan, Yu; Chen, Hongying; Dai, Hongwei; Li, Jie"
作者地址："[Li, Hanyue; Yuan, Yu; Chen, Hongying; Dai, Hongwei; Li, Jie] Chongqing Med Univ, Coll Stomatol, Chongqing 401147, Peoples R China; [Li, Hanyue; Yuan, Yu; Chen, Hongying; Dai, Hongwei; Li, Jie] Chongqing Med Univ, Chongqing Key Lab Oral Dis & Biomed Sci, Chongqing 401147, Peoples R China; [Li, Hanyue; Yuan, Yu; Chen, Hongying; Dai, Hongwei; Li, Jie] Chongqing Med Univ, Chongqing Municipal Key Lab Oral Biomed Engn Highe, Chongqing 401147, Peoples R China; [Dai, Hongwei; Li, Jie] Chongqing Med Univ, Coll Stomatol, 426 Songshibei Rd, Chongqing 401147, Peoples R China"
通信作者："Dai, HW; Li, J (通讯作者)，Chongqing Med Univ, Coll Stomatol, 426 Songshibei Rd, Chongqing 401147, Peoples R China."
ESI学科分类：BIOLOGY & BIOCHEMISTRY
关键词：Adipose-derived stromal; stem cells (ASCs); Experimental periodontitis; Macrophages; Indoleamine 2; 3-dioxygenase (IDO); Therapy
摘要："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-1b, 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 experi-mental periodontitis.(c) 2022 The Author(s). Published by Elsevier GmbH. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/)."
基金机构：National Natural Science Foundation of China; Scientific and Technological Research Program of Chongqing Municipal Education Commission; Natural Science Foundation of Chongqing Yuzhong District; ; [KJQN202000417]; 
基金资助正文："ACKNOWLEDGEMENT This study was supported by National Natural Science Foundation of China (No. 82071072) , Scientific and Technological Research Program of Chongqing Municipal Education Commission (No. KJQN202000417) and Natural Science Foundation of Chongqing Yuzhong District (No. 20200113) ."