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

Abstract

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.

Keywords: Berberine; CD4(+) T cells; Collagen-induced arthritis; Exosomes; Macrophage polarization; miR155.