Bardoxolone methyl breaks the vicious cycle between M1 macrophages and senescent nucleus pulposus cells through the Nrf2/STING/NF-κB pathway.
Int Immunopharmacol
; 127: 111262, 2024 Jan 25.
Article
de En
| MEDLINE
| ID: mdl-38101216
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.
Mots clés
Texte intégral:
1
Collection:
01-internacional
Base de données:
MEDLINE
Sujet principal:
Acide oléanolique
/
Dégénérescence de disque intervertébral
/
Nucleus pulposus
Limites:
Animals
Langue:
En
Journal:
Int Immunopharmacol
Sujet du journal:
ALERGIA E IMUNOLOGIA
/
FARMACOLOGIA
Année:
2024
Type de document:
Article
Pays de publication:
Pays-Bas