Abstract
A transplanted organ is usually rejected without any major immunosuppressive treatment because of vigorous alloimmune responsiveness. However, continuous global immunosuppression may cause severe side effects, including nephrotoxicity, tumors, and infections. Therefore, it is necessary to seek novel immunosuppressive agents, especially natural ingredients that may provide sufficient efficacy in immunosuppression with minimal side effects. Shikonin is a bioactive naphthoquinone pigment, an ingredient originally extracted from the root of Lithospermum erythrorhizon. Previous studies have shown that shikonin regulates immunity and exerts anti-inflammatory effects. In particular, it can ameliorate arthritis in animal models. However, it is unclear whether shikonin inhibits alloimmunity or allograft rejection. In this study and for the first time, we demonstrated that shikonin significantly prolonged the survival of skin allografts in wild-type mice. Shikonin increased the frequencies of CD4+Foxp3+ regulatory T cells (Tregs) post-transplantation and induced CD4+Foxp3+ Tregs in vitro as well. Importantly, depleting the Tregs abrogated the extension of skin allograft survival induced by shikonin. It also decreased the frequencies of CD8+CD44highCD62Llow effector T cells and CD11c+CD80+/CD11c+CD86+ mature DCs after transplantation. Moreover, we found that shikonin inhibited the proliferation of T cells in vitro and suppressed their mTOR signaling. It also reduced the gene expression of pro-inflammatory cytokines, including IFNγ, IL-6, TNFα, and IL-17A, while increasing the gene expression of anti-inflammatory mediators IL-10, TGF-β1, and indoleamine-2, 3-dioxygenase (IDO) in skin allografts. Further, shikonin downregulated IDO protein expression in skin allografts and DCs in vitro. Taken together, shikonin inhibits allograft rejection via upregulating CD4+Foxp3+ Tregs. Thus, shikonin is a novel immunosuppressant that could be potentially used in clinical transplantation.
Highlights
Organ transplantation is an effective and final treatment for patients undergoing end-stage organ diseases [1, 2]
We found that treatment with either shikonin or CsA obviously reduced overall cellular infiltration (Figure 1B) as well as CD3+ T-cell infiltration (Figure 1C) in the skin allografts compared to the control group, suggesting that shikonin prolongs skin allograft survival and reduces CD3+ T-cell infiltration in the allografts
We examined the effects of combined treatments with shikonin and low doses of CsA (10 mg/kg) or anti-CD45RB Ab (0.1 mg at day 0 & 5), and found that the double treatment was more effective in suppression of allograft rejection than shikonin alone while the triple treatment with all of three agents further prolonged allograft survival compared to the double treatment with either Shikonin+CsA or Shikonin+antiCD45RB Ab (Figure 1D)
Summary
Organ transplantation is an effective and final treatment for patients undergoing end-stage organ diseases [1, 2]. Almost all transplantation patients require continuous treatment with immunosuppressive drugs to prevent allograft rejection. Immunosuppressive agents play an essential role in maintaining allograft survival. Conventional immunosuppressive drugs can effectively suppress allograft rejection and improve the outcome of transplantation through different mechanisms [3]. Global immunosuppression may cause severe side effects. Adverse effects of an calcineurin inhibitor, such as cyclosporine (CsA), include nephrotoxicity, malignancies, hypertension, and infections [3,4,5] while rapamycin, an mTOR inhibitor, may result in hyperlipidemia, impaired glucose tolerance and diabetes, and acute renal toxicity [6, 7]. It is necessary to search for novel immunosuppressive agents that may provide high efficiency in immunosuppression with minimal side effects
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