Medical Prospect of Melatonin in the Intervertebral Disc Degeneration through Inhibiting M1-Type Macrophage Polarization via SIRT1/Notch Signaling Pathway
The study aims to explore the medical prospect of melatonin (MLT) and the underlying therapeutic mechanism of MLT-mediated macrophage (Mφ) polarization on the function of nucleus pulposus (NP) in intervertebral disc degeneration (IDD). RAW 264.7 Mφs were induced by lipopolysaccharide (LPS) to simula...
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MDPI AG
2023-06-01
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| Series: | Biomedicines |
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| Online Access: | https://www.mdpi.com/2227-9059/11/6/1615 |
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| author | Xinyu Dou Qipeng Luo Linzhen Xie Xuchang Zhou Chunyu Song Meijuan Liu Xiao Liu Yunlong Ma Xiaoguang Liu |
| author_facet | Xinyu Dou Qipeng Luo Linzhen Xie Xuchang Zhou Chunyu Song Meijuan Liu Xiao Liu Yunlong Ma Xiaoguang Liu |
| author_sort | Xinyu Dou |
| collection | DOAJ |
| description | The study aims to explore the medical prospect of melatonin (MLT) and the underlying therapeutic mechanism of MLT-mediated macrophage (Mφ) polarization on the function of nucleus pulposus (NP) in intervertebral disc degeneration (IDD). RAW 264.7 Mφs were induced by lipopolysaccharide (LPS) to simulate Mφ polarization and the inflammatory reaction of Mφs with or without MLT were detected. Conditioned medium (CM) collected from these activated Mφs with or without MLT treatment were further used to incubate NP cells. The oxidative stress, inflammation and extracellular matrix (ECM) metabolism in NP cells were determined. Then, the changes in SIRT1/Notch signaling were detected. The agonist (SRT1720) and inhibitor (EX527) of SIRT1 were used to further explore the association among MLT. The interaction between SIRT1 and NICD was detected by immunoprecipitation (IP). Finally, puncture-induced rat IDD models were established and IDD degrees were clarified by X-ray, MRI, H&E staining and immunofluorescence (IF). The results of flow cytometry and inflammation detection indicated that LPS could induce M1-type Mφ polarization with pro-inflammatory properties. MLT significantly inhibited the aforementioned process and inhibited M1-type Mφ polarization, accompanied by the alleviation of inflammation. Compared with those without MLT, the levels of oxidative stress, pro-inflammatory cytokines and ECM catabolism in NP cells exposed to CM with MLT were markedly downregulated in a dose-dependent manner. The inhibition of SIRT1 and the enhancement of Notch were observed in activated Mφs and they can be reversed after MLT treatment. This prediction was further confirmed by using the SRT1720 and EX527 to activate or inhibit the signaling. The interaction between SIRT1 and NICD was verified by IP. In vivo study, the results of MRI, Pfirrmann grade scores and H&E staining demonstrated the degree of disc degeneration was significantly lower in the MLT-treated groups when compared with the IDD control group. The IF data showed M1-type Mφ polarization decreased after MLT treatment. MLT could inhibit M1-type Mφ polarization and ameliorate the NP cell injury caused by inflammation in vitro and vivo, which is of great significance for the remission of IDD. The SIRT1/Notch signaling pathway is a promising target for MLT to mediate Mφ polarization. |
| first_indexed | 2024-03-11T02:45:09Z |
| format | Article |
| id | doaj.art-d45b07f48b574ab387bff93d1c77ad43 |
| institution | Directory Open Access Journal |
| issn | 2227-9059 |
| language | English |
| last_indexed | 2024-03-11T02:45:09Z |
| publishDate | 2023-06-01 |
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| series | Biomedicines |
| spelling | doaj.art-d45b07f48b574ab387bff93d1c77ad432023-11-18T09:25:46ZengMDPI AGBiomedicines2227-90592023-06-01116161510.3390/biomedicines11061615Medical Prospect of Melatonin in the Intervertebral Disc Degeneration through Inhibiting M1-Type Macrophage Polarization via SIRT1/Notch Signaling PathwayXinyu Dou0Qipeng Luo1Linzhen Xie2Xuchang Zhou3Chunyu Song4Meijuan Liu5Xiao Liu6Yunlong Ma7Xiaoguang Liu8Department of Orthopedics, Peking University Third Hospital, Beijing 100191, ChinaPain Medical Center, Peking University Third Hospital, Beijing 100191, ChinaPeking University Fourth School of Clinical Medicine, Beijing 100035, ChinaSchool of Sport Medicine and Rehabilitation, Beijing Sport University, Beijing 100084, ChinaDepartment of Anesthesiology, Peking University Third Hospital, Beijing 100191, ChinaDepartment of Endocrinology, Genetics and Metabolism, Beijing Children’s Hospital, Capital Medical University, National Center for Children’s Health, Beijing 100045, ChinaDepartment of Orthopedics, Peking University Third Hospital, Beijing 100191, ChinaPain Medical Center, Peking University Third Hospital, Beijing 100191, ChinaDepartment of Orthopedics, Peking University Third Hospital, Beijing 100191, ChinaThe study aims to explore the medical prospect of melatonin (MLT) and the underlying therapeutic mechanism of MLT-mediated macrophage (Mφ) polarization on the function of nucleus pulposus (NP) in intervertebral disc degeneration (IDD). RAW 264.7 Mφs were induced by lipopolysaccharide (LPS) to simulate Mφ polarization and the inflammatory reaction of Mφs with or without MLT were detected. Conditioned medium (CM) collected from these activated Mφs with or without MLT treatment were further used to incubate NP cells. The oxidative stress, inflammation and extracellular matrix (ECM) metabolism in NP cells were determined. Then, the changes in SIRT1/Notch signaling were detected. The agonist (SRT1720) and inhibitor (EX527) of SIRT1 were used to further explore the association among MLT. The interaction between SIRT1 and NICD was detected by immunoprecipitation (IP). Finally, puncture-induced rat IDD models were established and IDD degrees were clarified by X-ray, MRI, H&E staining and immunofluorescence (IF). The results of flow cytometry and inflammation detection indicated that LPS could induce M1-type Mφ polarization with pro-inflammatory properties. MLT significantly inhibited the aforementioned process and inhibited M1-type Mφ polarization, accompanied by the alleviation of inflammation. Compared with those without MLT, the levels of oxidative stress, pro-inflammatory cytokines and ECM catabolism in NP cells exposed to CM with MLT were markedly downregulated in a dose-dependent manner. The inhibition of SIRT1 and the enhancement of Notch were observed in activated Mφs and they can be reversed after MLT treatment. This prediction was further confirmed by using the SRT1720 and EX527 to activate or inhibit the signaling. The interaction between SIRT1 and NICD was verified by IP. In vivo study, the results of MRI, Pfirrmann grade scores and H&E staining demonstrated the degree of disc degeneration was significantly lower in the MLT-treated groups when compared with the IDD control group. The IF data showed M1-type Mφ polarization decreased after MLT treatment. MLT could inhibit M1-type Mφ polarization and ameliorate the NP cell injury caused by inflammation in vitro and vivo, which is of great significance for the remission of IDD. The SIRT1/Notch signaling pathway is a promising target for MLT to mediate Mφ polarization.https://www.mdpi.com/2227-9059/11/6/1615melatoninintervertebral disc degenerationmacrophage polarizationnucleus pulposus cellSIRT1/Notch signaling pathway |
| spellingShingle | Xinyu Dou Qipeng Luo Linzhen Xie Xuchang Zhou Chunyu Song Meijuan Liu Xiao Liu Yunlong Ma Xiaoguang Liu Medical Prospect of Melatonin in the Intervertebral Disc Degeneration through Inhibiting M1-Type Macrophage Polarization via SIRT1/Notch Signaling Pathway Biomedicines melatonin intervertebral disc degeneration macrophage polarization nucleus pulposus cell SIRT1/Notch signaling pathway |
| title | Medical Prospect of Melatonin in the Intervertebral Disc Degeneration through Inhibiting M1-Type Macrophage Polarization via SIRT1/Notch Signaling Pathway |
| title_full | Medical Prospect of Melatonin in the Intervertebral Disc Degeneration through Inhibiting M1-Type Macrophage Polarization via SIRT1/Notch Signaling Pathway |
| title_fullStr | Medical Prospect of Melatonin in the Intervertebral Disc Degeneration through Inhibiting M1-Type Macrophage Polarization via SIRT1/Notch Signaling Pathway |
| title_full_unstemmed | Medical Prospect of Melatonin in the Intervertebral Disc Degeneration through Inhibiting M1-Type Macrophage Polarization via SIRT1/Notch Signaling Pathway |
| title_short | Medical Prospect of Melatonin in the Intervertebral Disc Degeneration through Inhibiting M1-Type Macrophage Polarization via SIRT1/Notch Signaling Pathway |
| title_sort | medical prospect of melatonin in the intervertebral disc degeneration through inhibiting m1 type macrophage polarization via sirt1 notch signaling pathway |
| topic | melatonin intervertebral disc degeneration macrophage polarization nucleus pulposus cell SIRT1/Notch signaling pathway |
| url | https://www.mdpi.com/2227-9059/11/6/1615 |
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