Berberine Prolongs Mouse Heart Allograft Survival by Activating T Cell Apoptosis via the Mitochondrial Pathway

Abstract

Berberine, which is a traditional Chinese medicine can inhibit tumorigenesis by inducing tumor cell apoptosis. However, the immunoregulatory of effects berberine on T cells remains poorly understood. Here, we first examined whether berberine can prolong allograft survival by regulating the recruitment and function of T cells. Using a major histocompatibility complex complete mismatch mouse heterotopic cardiac transplantation model, we found that the administration of moderate doses (5 mg/kg) of berberine significantly prolonged heart allograft survival to 19 days and elicited no obvious berberine-related toxicity. Compared to that with normal saline treatment, berberine treatment decreased alloreactive T cells in recipient splenocytes and lymph node cells. It also inhibited the activation, proliferation, and function of alloreactive T cells. Most importantly, berberine treatment protected myocardial cells by decreasing CD4+ and CD8+ T cell infiltration and by inhibiting T cell function in allografts. In vivo and in vitro assays revealed that berberine treatment eliminated alloreactive T lymphocytes via the mitochondrial apoptosis pathway, which was validated by transcriptome sequencing. Taken together, we demonstrated that berberine prolongs allograft survival by inducing apoptosis of alloreactive T cells. Thus, our study provides more evidence supporting the potential use of berberine in translational medicine.

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“…Anti-PD-1 mAb combined with apigenin could effectively enhance the cytotoxic effect of CD8+ T cells with an increased level of TNF-α, IFN-γ, and granzyme B in the Lewis lung carcinoma model that did not respond to treatment with anti-PD-1 mAb alone [87]. Berberine (BBR), an isoquinoline alkaloid derived from Coptidis chinensis Franch and Phellodendron chinense Schneid, exerts an anti-tumor effect on many cell types (e.g., non-small-cell lung cancer (NSCLC) cells and breast cancer cells), of which the anti-tumor effect is abolished in T-cell-deficient mice models, suggesting that immunomodulatory effects of BBR are associated with T cell action [88]. Liu et al found that BBR could promote PD-L1 degradation through the ubiquitin/proteasome-dependent pathway and inhibit the PD-1/PD-L1 axis through deubiquitination activity, resulting in effective down-regulation of PD-L1 expression and counteraction of IFN-γ-induced PD-L1 upregulation in vitro and in vivo [89].…”

Berberine up‐regulates miR‐340‐5p to protect myocardial ischaemia/reperfusion from HMGB1‐mediated inflammatory injury

“…Berberine (BBR) is a quaternary ammonium alkaloid extracted from Rhizoma coptidis with multiple biochemical and pharmacological activities, including anti‐apoptosis and cardioprotective effects. 7 , 8 , 9 , 10 Notably, the effects of BBR on MIRI have attracted the attention of researchers. For instance, Zhu et al revealed that BBR could protect against MIRI via promoting cardiomyocytes proliferation and suppressing the apoptosis.…”

“…Berberine (BBR) is a quaternary ammonium alkaloid extracted from Rhizoma coptidis with multiple biochemical and pharmacological activities, including anti‐apoptosis and cardioprotective effects 7–10 . Notably, the effects of BBR on MIRI have attracted the attention of researchers.…”