Journal of periodontology · 2024
Beyond transcription, aryl hydrocarbon receptor plays a protective role in periodontitis by interacting with CaMKII.
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Zeng Xuwen, Feng Meiting, Lu Jiawei, Wang Ruiling, Deng Li, Yang Yanan, Luo Lijun
Аннотация
BACKGROUND: The aryl hydrocarbon receptor (AhR) has been studied as an intracellular pattern recognition receptor that can identify bacterial pigments. To identify a potential therapeutic target for periodontitis, we investigated the expression of AhR in periodontitis and its role in the pathogenesis of periodontitis.
METHODS: First, we analyzed AhR expression in a single-cell dataset from human periodontal tissue. Quantitative polymerase chain reaction (qPCR), immunofluorescence, and immunohistochemistry were used to verify the AhR level. Later, we determined the phenotypes of ligature-induced periodontitis in myeloid-specific AhR-deficient mice (Lyz2-Cre+/- AhRfx/fx), after which RNA sequencing (RNA-seq), qPCR, Western blot, immunofluorescence, and immunohistochemistry were used to investigate the impacts of AhR on periodontitis and its mechanism. Finally, we determined the therapeutic effect of AhR agonist 6-Formylindolo[3,2-b]carbazole (FICZ) administration on murine periodontitis and verified the effects of FICZ on macrophage polarization in vitro.
RESULTS: AhR expression was enhanced in macrophages from periodontitis patients. Deletion of AhR from macrophages aggravated ligature-induced periodontitis and promoted the inflammatory response. Calcium/calmodulin-stimulated protein kinase II (CaMKII) phosphorylation was accelerated in AhR-deficient macrophages. Inhibiting CaMKII phosphorylation ameliorated periodontitis in Lyz2-Cre+/- AhRfx/fx mice. FICZ treatment blocked alveolar bone loss and relieved periodontal inflammation. FICZ diminished M1 macrophage polarization and promoted M2 macrophage polarization upon M1 macrophage induction.
CONCLUSION: AhR played a protective role in the pathogenesis of periodontitis by orchestrating macrophage polarization via interacting with the CaMKII signaling pathway.
METHODS: First, we analyzed AhR expression in a single-cell dataset from human periodontal tissue. Quantitative polymerase chain reaction (qPCR), immunofluorescence, and immunohistochemistry were used to verify the AhR level. Later, we determined the phenotypes of ligature-induced periodontitis in myeloid-specific AhR-deficient mice (Lyz2-Cre+/- AhRfx/fx), after which RNA sequencing (RNA-seq), qPCR, Western blot, immunofluorescence, and immunohistochemistry were used to investigate the impacts of AhR on periodontitis and its mechanism. Finally, we determined the therapeutic effect of AhR agonist 6-Formylindolo[3,2-b]carbazole (FICZ) administration on murine periodontitis and verified the effects of FICZ on macrophage polarization in vitro.
RESULTS: AhR expression was enhanced in macrophages from periodontitis patients. Deletion of AhR from macrophages aggravated ligature-induced periodontitis and promoted the inflammatory response. Calcium/calmodulin-stimulated protein kinase II (CaMKII) phosphorylation was accelerated in AhR-deficient macrophages. Inhibiting CaMKII phosphorylation ameliorated periodontitis in Lyz2-Cre+/- AhRfx/fx mice. FICZ treatment blocked alveolar bone loss and relieved periodontal inflammation. FICZ diminished M1 macrophage polarization and promoted M2 macrophage polarization upon M1 macrophage induction.
CONCLUSION: AhR played a protective role in the pathogenesis of periodontitis by orchestrating macrophage polarization via interacting with the CaMKII signaling pathway.