Metabolic reprogramming as a key regulator in the pathogenesis of rheumatoid arthritis.

PURPOSE: Rheumatoid arthritis (RA) is a chronic, systemic autoimmune disease with synovitis as pathological changes. The immune microenvironment of RA promotes metabolic reprogramming of immune cells and stromal cells, which leads to dysfunction and imbalance of immune homeostasis. Cell metabolism undergoes the switch from a static regulatory state to a highly metabolic active state, which changes the redox-sensitive signaling pathway and also leads to the accumulation of metabolic intermediates, which in turn can act as signaling molecules and further aggravate the inflammatory response. The reprogramming of immunometabolism affects the function of immune cells and is crucial to the pathogenesis of RA. In addition, mitochondrial dysfunction plays a key role in glycolytic reprogramming in RA. These metabolic changes may be potential therapeutic targets for RA. Therefore, we reviewed the metabolic reprogramming of RA immune cells and fibroblast-like synovium cells (FLS) and its relationship with mitochondrial dysfunction. METHODS: A computer-based online search was performed using the PubMed database and Web of Science database for published articles concerning immunometabolic reprogramming, mitochondrial dysfunction, and rheumatoid arthritis. RESULTS: This article reviews the metabolic reprogramming of immune cells and fibroblast-like synoviocytes in RA and their relationship to mitochondrial disfunction, as well as the key pro-inflammatory pathways associated with metabolic reprogramming and chemotherapy as a potential future therapeutic strategy for RA.

Berberine modulates the immunometabolism and differentiation of CD4+ T cells alleviating experimental arthritis by suppression of M1-exo-miR155.

BACKGROUND: The inflammatory cascade mediated by macrophages and T cells is considered to be an important factor in promoting the progression of rheumatoid arthritis (RA). Our previous study found that berberine (BBR) can therapeutically impact adjuvant arthritis (AA) in rats through the regulation of macrophage polarization and the balance of Th17/Treg. However, whether BBR's effects on CD4+T cells response are related to its suppression of M1 macrophage still unclear. PURPOSE: The study aimed to estimate the mechanism of BBR in regulating the immunometabolism and differentiation of CD4+T cells are related to exosome derived from M1-macrophage (M1-exo). STUDY-DESIGN/METHODS: Mice model of collagen-induced arthritis (CIA) was established to investigate the antiarthritic effect of BBR was related with regulation of M1-exo to balance T cell subsets. Bioinformatics analysis using the GEO database and meta-analysis. In vitro, we established the co-culture system involving M1-exo and CD4+ T cells to examine whether BBR inhibits CD4+T cell activation and differentiation by influencing M1-exo-miR155. Exosome was characterized using transmission electron microscopy and western blot analysis, macrophage and CD4+T cell subpopulation were detected by flow cytometry. Further, the metabolic profiles of CD4+T cells were assessed by ECAR, OCR, and the level of glucose, lactate, intracellular ATP. RESULT: BBR reinstates CD4+ T cell homeostasis and reduces miR155 levels in both M1-exo and CD4+ T cells obtained from mice with CIA. In vitro, we found exosomes are indispensable for M1-CM on T lymphocyte activation and differentiation. BBR reversed M1-exo facilitating the activation and differentiation of CD4+T cells. Furthermore, BBR reversed glycolysis reprogramming of CD4+T cells induced by M1-exo, while these regulation effects were significantly weakened by miR155 mimic. CONCLUSION: The delivery of miR-155 by M1-exo contributes to CD4+ T cell immunometabolism dysfunction, a process implicated in the development of RA. The anti-arthritic effect of BBR is associated with the suppression of glycolysis and the disruption of CD4+ T cell subsets balance, achieved by reducing the transfer of M1-exo-miR155 into T cells.

Berberine ameliorates collagen-induced arthritis in mice by restoring macrophage polarization via AMPK/mTORC1 pathway switching glycolytic reprogramming.

Dysfunction of macrophage polarization majorly contributes to the progression of rheumatoid arthritis (RA). Polarization and functions of activated macrophages are closely associated with the reprogramming of intracellular metabolisms. Previously, we demonstrated that the anti-arthritis effect of berberine (BBR) in rats with adjuvant-induced arthritis (AA) may be related to AMP-activated protein kinase (AMPK) activation (a key regulator in the biological energy metabolism), and balanced macrophage polarization. However, the specific molecular mechanism of BBR in macrophage metabolism is yet to be elucidated. In this study, we clarified that BBR ameliorated articular inflammation and restored M1/M2 ratio in collagen-induced arthritis (CIA) mice in an AMPK-dependent manner. Mechanistically, BBR reversed the effects of mTORC1 agonist leucine (Leu) on regulating macrophage polarization through activation of AMPK to switch glycolytic reprogramming. Furthermore, BBR inhibition of mTORC1 rely on activation of AMPK to phosphorylate raptor and TSC2 instead of destroying its structure. Our study revealed that the activation of AMPK is required for the BBR-mediated anti-arthritis effect by downregulating mTORC1/HIF-1α and inhibiting the glycolysis in M1 macrophages.