Low-Protein Diet Inhibits the Synovial Tissue Macrophage Pro-Inflammatory Polarization Via NRF2/SIRT3/SOD2/ROS Pathway in K/BxN Rheumatoid Arthritis Mice.
Study Goal
The researchers aimed to determine whether a low-protein diet could alleviate rheumatoid arthritis symptoms by modulating macrophage polarization and the NRF2/SIRT3/SOD2 pathway.
Results Summary
The study found that a low-protein diet significantly reduced RA symptoms, decreased pro-inflammatory cytokines, inhibited M1 macrophage polarization, and promoted M2 macrophage shift via the NRF2/SIRT3/SOD2 pathway, reducing mitochondrial ROS production. NRF2 knockdown abolished these effects, confirming its central role.
Population
Arthritic transgenic K/BxN mice and naive mice used to establish a rheumatoid arthritis model.
Effective Dosage
Not specified
Duration
Not specified
Interactions
None mentioned
| Intervention | Direction | Endpoint | Population | Dosage | Impact | Claim # |
|---|---|---|---|---|---|---|
low-protein diet | decrease | disease symptoms | K/BxN rheumatoid arthritis model mice | - | significantly alleviates | #1 |
low-protein diet | decrease | pro-inflammatory cytokine levels in synovial fluid | K/BxN rheumatoid arthritis model mice | - | decreases | #2 |
low-protein diet | decrease | M1 macrophage polarization | K/BxN rheumatoid arthritis model mice | - | inhibits | #3 |
low-protein diet | increase | M2 phenotype | K/BxN rheumatoid arthritis model mice | - | promoting a shift towards | #4 |
low protein treatment | increase | NRF2 | in vitro | - | promote the activity of | #5 |
low protein treatment | decrease | ubiquitin mediated proteolysis | in vitro | - | inhibiting | #6 |
low protein treatment | increase | NRF2/SIRT3/SOD2 pathway | in vitro | - | activate | #7 |
low protein treatment | decrease | production of ROS | in vitro | - | inhibit | #8 |
low protein treatment | decrease | M1 macrophage polarization | in vitro | - | inhibit | #9 |
low-protein diet | decrease | synovial macrophage M1 polarization | - | - | inhibit | #10 |
low-protein diet | decrease | mitochondrial ROS production | - | - | reduce | #11 |
low-protein diet | decrease | synovial inflammation | - | - | decreases | #12 |
low-protein diet | decrease | RA symptoms | - | - | alleviates | #13 |
Rheumatoid arthritis (RA) is a chronic inflammatory disorder characterized by pain, swelling, stiffness, and impaired function. Attenuating inflammation is a crucial objective in RA management. Diet and nutrition are believed to influence RA symptomatology, with a low-protein diet being one potential nutritional strategy, although its underlying mechanisms remain to be fully elucidated. In this research, serum derived from arthritic transgenic K/BxN mice was administered to naive mice to establish a K/BxN rheumatoid arthritis model. Physiological assessments and histological staining were performed to evaluate joint pathology. (Enzyme-linked immunosorbent assay) ELISA was used to measure inflammatory cytokines. Flow cytometry and immunofluorescence were applied to characterize macrophage phenotypes. Transcriptomic analysis elucidated molecular pathways under the effect of a low-protein diet and verified by immunoblotting. Mitochondrial reactive oxygen species (ROS) was detected by Mito-SOX. Protein expression was silenced through the application of siRNA transfection. Our results indicate that a low-protein diet significantly alleviates disease symptoms and decreases pro-inflammatory cytokine levels in synovial fluid. Furthermore, this dietary intervention inhibits M1 macrophage polarization while promoting a shift towards the M2 phenotype. Transcriptomic analysis revealed that the beneficial effects of the low-protein diet in alleviating rheumatoid arthritis are closely linked to the NRF2 pathway. In vitro, low protein treatment can promote the activity of NRF2 via inhibiting the ubiquitin mediated proteolysis and activate the NRF2/SIRT3/SOD2 pathway to inhibit the production of ROS, which will further inhibit the M1 macrophage polarization. NRF2 knockdown can abolish the effects of low-protein treatment, indicating that the inhibition of M1 polarization and the anti-inflammatory response induced by low-protein treatment are dependent on NRF2. In summary, our findings propose that low-protein diet can inhibit synovial macrophage M1 polarization via activating NRF2/SIRT3/SOD2 pathway to reduce mitochondrial ROS production. This mechanism effectively decreases synovial inflammation and alleviates RA symptoms.