Abstract
The expansion of myeloid-derived suppressor cells (MDSCs) has been documented in murine models and patients with lupus nephritis (LN), but the exact role of MDSCs in this process remains largely unknown. In this study, we investigated whether MDSCs are involved in the process of podocyte injury in the development of LN. In toll-like receptor-7 (TLR-7) agonist imiquimod-induced lupus mice, we found the severe podocyte injury in glomeruli of lupus mice and significant expansion of MDSCs in spleens and kidneys of lupus mice. The function of TLR-7 activated MDSCs was enhanced including the increased generation of reactive oxygen species (ROS) in vivo and in vitro. Moreover, the ROS production of MDSCs induced podocyte injury through activating the p-38MAPK and NF-kB signaling. Furthermore, we verified that podocyte injury was indeed correlated with expansion of MDSCs and their ROS secretion in LN of pristane-induced lupus mice. These findings first indicate that the podocyte injury in LN was associated with the increased MDSCs in kidney and MDSCs may be a promising therapeutic target of LN in the future.
Highlights
Systemic lupus erythematosus (SLE) is a typical autoimmune disease and mostly occurs in females (9:1 prevalence) around child-bearing age [1]
The expression of vascular endothelial growth factor (VEGF) was measured by quantitative real-time RT-PCR (qRT-PCR) and the results showed that the down-regulated expression of VEGF in podocytes co-cultured with R848-treated myeloid-derived suppressor cells (MDSCs) (Figure 3F)
The results showed that the expression of WT-1 and nephrin was increased, while the expression of IL-1β, IL-6, and TNF-α was reduced in podocytes co-cultured with MDSCs pretreated with NAC before treatment with R848, compared with control group, and co-cultured with MDSCs treated with R848 (Figure 4D)
Summary
Systemic lupus erythematosus (SLE) is a typical autoimmune disease and mostly occurs in females (9:1 prevalence) around child-bearing age [1]. Lupus nephritis (LN), one of the most severe manifestations of SLE, is characterized by proteinuria, hematuria, and renal failure caused by deposition of immune complexes and tightly associated with high morbidity and mortality [2,3,4]. Only 50–70% of patients with LN achieved remission and 10–20% of patients will progress to end-stage renal disease within 5 years of diagnosis [5]. Myeloid-derived suppressor cells (MDSCs) are a heterogeneous collection of myeloid cells comprised myeloid precursors, immature granulocytes, mononuclear macrophages, and dendritic cells [6, 7]. MDSCs are broadly characterized by CD11b+ Gr-1+ cells in mice and HLA-DR−CD11b+CD33+ cells in humans, which further divided into granulocytic polymorphonuclear MDSCs (G-MDSCs)
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