2,3,7,8 tetrachlorodibenzo-p-dioxin (TCDD)-induced myeloid derived suppressor cells (MDSC) have heightened metabolic activity which correlates with microRNA and gene expression involved in immunosuppression

Abstract

Abstract Myeloid-derived suppressor cells (MDSCs) are bone marrow (BM)-derived cells consisting of monocytic (M-MDSC) or granulocytic (G-MDSC) subtypes with immunosuppressive activity. In the current study, we examined the metabolism and functions of MDSCs induced by TCDD a highly toxic environmental pollutant. Inasmuch, we injected mice with either vehicle or 10μg/kg TCDD interpersonally and found that TCDD increased both M-MDSCs and G-MDSCs in the peritoneal exudate when compared to controls. We determined the cell bioenergetics in TCDD-induced MDSCs when compared to naïve BM-MDSCs. For this purpose, we examined the mitochondrial oxygen consumption rate (OCR) and found that TCDD-induced MDSCs had heightened basal respiration, ATP-linked respiration, proton (H+) leak, maximal respiration, spare respiratory capacity as well as total proton efflux rate (PER) which means more suppressive function when compared to BM-MDSCs. We next examined whether the heightened metabolic potential in TCDD-induced MDSCs correlated with the microRNA and gene expression. MiRNA array analysis demonstrated that in TCDD-induced MDSCs, certain miRNAs (e.g. mir-543-3p, mir-150-5p) were downregulated which target immunosuppressive genes involved in MDSC functions, such as ARG2, IL-10, STAT-3, and PIM1. Next, we investigated the role of miRNA-150-5p in IL-10, PIM1, and STAT3 expression as well as miRNA-543-3p effects on ARG2 using transfection experiments. We found that MDSCs transfected with mature miRNA-150-5p and miRNA-543-3p were downregulated whereas inhibitors upregulated the expression of respective targets. In summary, our data revealed that TCDD modulates miRNA expression which can impact gene expression and metabolism in MDSC.