Ferumoxytol Attenuates the Function of MDSCs to Ameliorate LPS-Induced Immunosuppression in Sepsis

Yaxian Xue,Huan Dou,Yayi Hou,Yujun Xu,Huaping Liang,Xia Lu,Zhiheng Sun,Yuchen Pan,Xinghan Liu

doi:10.1186/s11671-019-3209-2

Yaxian Xue, Huan Dou + Show 7 more

Open Access

https://doi.org/10.1186/s11671-019-3209-2

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Abstract

Sepsis-induced immunosuppression is recognized as one of the main features responsible for therapeutic failures. Myeloid-derived suppressor cells (MDSCs), which are mainly characterized by their suppressive properties, have been reported to be expanded in sepsis. Ferumoxytol (FMT), an FDA-approved iron supplement, has been shown to possess immune-modulatory properties in tumors. However, it is unclear whether FMT alters the functions of MDSCs to reduce late-sepsis immunosuppression. Here, we showed an immunomodulatory effect of FMT on MDSCs to ameliorate lipopolysaccharide (LPS)–induced immunosuppression in the late stage of sepsis. Separation of cells with internalized FMT and detection of the intracellular iron content showed that MDSCs could uptake FMT. Low doses of FMT had no effects on the cell viability of MDSCs, but FMT inhibited the expansion of MDSCs in vitro. Moreover, FMT significantly downregulated the expression levels of Arg-1, S100A8, S100A9, and p47phox as well as ROS production in MDSCs. FMT decreased the percentage of granulocytic MDSCs (G-MDSCs) and promoted the differentiation of MDSCs into macrophages. Furthermore, FMT reduced white blood cell recruitment and alveolar wall thickening in the lungs and areas of necrosis in the liver as well as some biochemical markers of liver dysfunction. FMT decreased the percentage of G-MDSCs and monocytic MDSCs (M-MDSCs) in the spleens of LPS-induced septic mice. Of note, FMT reduced the T cell immunosuppressive functions of both G-MDSCs and M-MDSCs. Expectedly, FMT also significantly reduced Arg-1 and p47phox gene expression in splenic CD11b+Gr-1+ cells isolated from LPS-challenged mice. These data indicate that FMT decreased the immunosuppressive functions of MDSCs by decreasing Arg-1 and ROS production, suggesting that FMT may reduce long-term immunosuppression in the late stage of sepsis.

Highlights

FMT, an iron supplement approved by the Food and Drug Administration, has been used for treating iron deficiency anemia in adults with chronic kidney disease (CKD) [1], and FMT is widely used as a contrast agent and drug carrier [2]
A Large Number of Myeloid-derived suppressor cell (MDSC) Uptake FMT To verify whether cells with FMT internalized are separated by MACS MicroBeads, we used Prussian blue staining to detect intracellular iron content in macrophages treated with FMT (1000 ng/mL) for 24 h
Flow cytometric analysis revealed that nearly 60% of MDSCs and more than 60% of macrophages accumulated FMT after 12–48 h (Fig. 1b, c)

Summary

Introduction

FMT, an iron supplement approved by the Food and Drug Administration, has been used for treating iron deficiency anemia in adults with chronic kidney disease (CKD) [1], and FMT is widely used as a contrast agent and drug carrier [2]. Previous studies showed that FMT had immunomodulatory properties, such as its MDSCs are a heterogeneous population of immature myeloid cells with a potent immune suppressive capacity [5]. MDSCs consist of two large groups of cells, granulocytic or PMN-MDSCs and M-MDSCs, and both populations have immune suppressive functions through the production of iNOS, ROS, and Arg-1. INOS generates NO, which inhibits the functions of both JAK3 and STAT6 in T cells, as well as the expression of MHC II. A high level of fluorescent nanoparticle uptake by MDSCs in the esophagus and spleen of mice was reported in imaging studies [10]. It is unclear whether FMT alters the function of MDSCs involved in the development of inflammatory diseases

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