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 attenuates arthritis in adjuvant-induced arthritic rats associated with regulating polarization of macrophages through AMPK/NF-кB pathway.

Berberine (BBR) is a traditional folk medicine with excellent anti-inflammatory properties. This study aimed to investigate the anti-arthritic effects of BBR in adjuvant arthritis (AA) in rats and its regulatory role in the polarization of macrophages. Rats were immunized with Complete Freund's Adjuvant (CFA), and then BBR (40, 80, 160 mg/kg) was administered orally for 14 days. BBR significantly reduced paw swelling and arthritis global assessment as well as alleviated joint destruction and inflammatory cell infiltration. The index of the thymus and thymocyte proliferation were significantly reduced by BBR. Moreover, BBR treatment restrained the phagocytic function of macrophages and restored the balance of M1/M2 by reducing the levels of M1 cytokines (tumour necrosis factor-α, interleukin-1ß, and interleukin-6), increasing the levels of M2 cytokines (interleukin-10 and transforming growth factor-ß1), increasing the expression of arginase 1(Arg1) (M2 marker) and decreasing the expression of inducible nitric oxide synthase (iNOS) (M1 marker). BBR also downregulated the ratio of Th17/Treg cells. Further research on the adenosine 5'-monophosphate (AMP)-activated protein kinase (AMPK)/nuclear factor κB (NF-κB) pathway found that BBR upregulated the activity of AMPK, while it downregulated the expression of phospho-RelA (p-p65), phospho-NF-kappa-B inhibitor alpha (p-IκBα) and cyclooxygenase (COX)-2. Therefore, our findings suggest BBR has significantly therapeutic effects in AA rats by regulating the polarization of macrophages through the AMPK/NF-кB pathway.