Abstract
This study is aimed at investigating the effects of shikonin, a pyruvate kinase M2 (PKM2) inhibitor, on the functions of myeloid dendritic cells (mDCs) in a mouse model of severe aplastic anemia (AA) generated by total body irradiation and lymphocyte infusion. Flow cytometry and qPCR were used to determine the proportions of PKM2+ mDCs and other immune indicators in the AA mice. Glucose consumption level, pyruvate generation level, and ATP content were used to determine the level of glycolytic metabolism in the mDCs. The survival rates of AA mice were evaluated after the administration of shikonin or the immunosuppressive agent cyclosporin A. The AA mice displayed pancytopenia, decreased CD4+/CD8+ cell ratio, increased perforin and granzyme levels in CD8+ cells, increased costimulatory CD80 and CD86 expressions, and inadequate regulatory T cell number. In vivo animal experiments showed that the shikonin-mediated inhibition of the PKM2 expression in mice was associated with high survival rates. In addition, the administration of cyclosporin A or shikonin decreased the expression of cytotoxic molecules and costimulatory CD80 and CD86 on CD8+ cells. Taken together, the results of this study indicated that shikonin could inhibit the activation and proliferation of mDCs as well as the activation of downstream cytotoxic T cells by reducing the PKM2 level in mDCs.
Highlights
Severe aplastic anemia (SAA) is a class of highly heterogeneous hematological diseases with complex etiology and pathogenesis [1]
The AA mice were treated with shikonin or cyclosporin A (CsA), and the results showed that shikonin affected the function of myeloid dendritic cells (mDCs) and cytotoxic T lymphocytes (CTLs) in vivo
pyruvate kinase M2 (PKM2)+ mDCs Increased in the AA Mice and Decreased after Shikonin Treatment
Summary
Severe aplastic anemia (SAA) is a class of highly heterogeneous hematological diseases with complex etiology and pathogenesis [1]. SAA patients exhibit abnormally high levels of activated myeloid dendritic cells (mDCs) that secrete inflammatory factors involved in the generation and activation of T cells This overactivation of mDCs and T lymphocytes leads to the failure of bone marrow hematopoietic function [2, 3]. Shikonin has been shown to inhibit liver cancer by causing mitochondrial dysfunction and increasing the oxidative stress level in tumor cells [8]. Apart from it antitumor activity, shikonin has been shown to have therapeutic effects against HIV infection, psoriasis, and other autoimmune diseases, but their underlying mechanisms are still unclear. In this study, we focused on investigating the effect of shikonin on the immune status of SAA
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