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Published on: March 30, 2018
Bardoxolone methyl breaks the vicious cycle between M1 macrophages and senescent nucleus pulposus cells through the
Peng Wang1, Shuo Zhang1, Weijian Liu1
1Department of Orthopaedics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China.
Abstract:
Intervertebral disc (IVD) degeneration (IDD), an age-related degenerative disease, is accompanied by the accumulation of senescent nucleus pulposus (NP) cells and extracellular matrix (ECM) degradation. The current study aims to clarify the role of M1 macrophages in the senescence of NP cells, and further explores whether bardoxolone methyl (CDDO-Me) can alleviate the pathological changes induced by M1 macrophages and relieve IDD. On the one hand, conditioned medium (CM) of M1 macrophages (M1CM) triggered senescence of NP cells and ECM degradation in a time-dependent manner. On the other hand, CM of senescent NP cells (S-NPCM) was collected to treat macrophages and we found that S-NPCM promoted the migration and M1-polarization of macrophages. However, both of the above effects can be partially blocked by CDDO-Me. We further explored the mechanism and found that M1CM promoted the expression level of STING and nuclear translocation of P65 in NP cells, while being restrained by CDDO-Me and STING inhibitor H151. In addition, the employment of Nrf2 inhibitor ML385 facilitated the expression level of STING and nuclear translocation of P65, thereby blocking the effects of CDDO-Me on suppressing senescence of NP cells and ECM degradation. In vivo, the injection of CDDO-Me into the disc decreased the infiltration of M1 macrophages and ameliorated degenerative manifestations in the puncture-induced rat IDD model. In conclusion, CDDO-Me was proved to break the vicious cycle between M1 macrophages and senescent NP cells through the Nrf2/STING/NF-κB pathway, thereby attenuating the progression of IDD.
Insights
Bardoxolone methyl (CDDO-Me) breaks the cycle between M1 macrophages and senescent nucleus pulposus cells, reducing intervertebral disc degeneration (IDD) by targeting the Nrf2/STING/NF-κB pathway.
Area of Science:
- Biomedical Science
- Cell Biology
- Immunology
Background:
- Intervertebral disc degeneration (IDD) involves senescent nucleus pulposus (NP) cells and extracellular matrix (ECM) degradation.
- M1 macrophages contribute to NP cell senescence and ECM breakdown in IDD.
Purpose of the Study:
- To investigate the role of M1 macrophages in NP cell senescence and IDD.
- To explore bardoxolone methyl (CDDO-Me) as a potential therapeutic agent for IDD by modulating M1 macrophage activity.
Main Methods:
- M1 macrophage conditioned medium (M1CM) and senescent NP cell conditioned medium (S-NPCM) were used to study cellular interactions.
- CDDO-Me, STING inhibitor (H151), and Nrf2 inhibitor (ML385) were employed to investigate molecular mechanisms.
- In vivo studies utilized a puncture-induced rat IDD model to assess CDDO-Me efficacy.
Main Results:
- M1CM induced NP cell senescence and ECM degradation; S-NPCM promoted M1 macrophage migration and polarization.
- CDDO-Me partially blocked these effects by inhibiting STING and NF-κB (P65) activation.
- CDDO-Me's therapeutic action involves the Nrf2/STING/NF-κB pathway, reducing M1 macrophage infiltration and IDD in vivo.
Conclusions:
- CDDO-Me effectively attenuates IDD by disrupting the M1 macrophage-senescent NP cell feedback loop.
- The Nrf2/STING/NF-κB pathway is a critical target for CDDO-Me in treating IDD.
