MDSCs Induce Podocyte Injury Through Increasing Reactive Oxygen Species In Lupus Nephritis

Systemic lupus erythematosus(SLE)is a chronic autoimmune disease that is characterized by disorders of multiple organs and systems.Renal involvement,termed lupus nephritis(LN),is a representative tissue disorder of SLE.Clinically,LN is characterized by proteinuria,hematuria,and renal failure,potentially leading to end-stage kidney disease and the need for dialysis or renal transplantation.The pathogenesis of LN is complex,while podocytes injury is an important factor in renal injury of lupus nephritis.Podocytes,also known as glomerular visceral epithelial cells,form the glomerular filtration barrier(GFB)together with glomerular basement membrane(GBM)and glomerular capillary endothelial cells to maintain the selective permeability of the glomerular capillary to albumin.Once the podocytes are damaged,the functions will be destroyed,eventually leading to a lot of proteinuria,and renal dysfunction.Myeloid-derived suppressor cells(MDSCs),are an immature,heterogeneous myeloid cell population,which are considered to possess immunosuppressive function.In recent years,a lot of reports have been extensively studied about the role of MDSCs in multiplex autoimmune diseases such as rheumatoid arthritis,type Ⅰdiabetes,systemic sclerosis,and systemic lupus erythematosus and these studies have shown that the number and function of MDSCs have changed significantly in diseases process and MDSCs participat in disease progression by involving in regulating the immune system of the patients.Moreover,with the deepening of research,it is found that the function of MDSCs is not limited to immunosuppression.But,the role of MDSCs in the development of lupus nephritis is rarely reported so far.Although some reports revealed that MDSCs take part in the regulation of lupus nephritis,these studies draw a different conclusion on the role of MDSCs in LN and the exhaustive role of MDSCs are not mentioned.Moreover there is no report on the relationship between MDSCs and apparent podocyte damage in LN.And so the role of MDSCs in the progression of LN remains confused and further exploration are urgently needed.Therefore,the aim of this study is to analyze the changes in the number and function of MDSCs in LN and explore the effect of MDSCs on podocytes,and further determine the role of MDSCs in lupus nephritis.Significant kidney injury and expansion of MDSCs in imiquimod-induced lupus-like model mice:We first constructed the TLR-7 agonist imiquimod-induced lupus-like mouse model,and found that the model mice showed significant renal injury symptoms,including severe podocyte injury.At the same time,the proportion of MDSCs in spleen and kidney was significantly increased,and the expression levels of ROS,iNOS and Arg-1 were also up-regulated in MDSCs,which indicate that the function of MDSCs is enhanced.Podocyte injury induced by TLR-7 activated MDSCs is mediated by releasing ROS:To investigate the effect of MDSCs on renal injury in model mice,we then conduct experiments in vitro,which demonstrate that TLR-7 agonist R848-treated MDSCs induce podocytes injury when co-cultured with podocytes.Evidence of podocyte injury are as follows:changes in podocyte morphology,downregulation of podocyte-specific marker,changes in podocyte phenotype,downregulation of podocyte function molecule VEGF,podocyte apoptosis,upregulation of inflammatory factor in podocyte.Moreover we found that,TLR-7 agonist R848 can significantly up-regulate MDSCs functional molecules such as ROS,iNOS,Arg-1,which consistents with the results of model mice.We also found that the injury of podocytes induced by MDSCs was significantly ameliorated after using ROS inhibitor NAC,which indicates that TLR-7 activated MDSCs promote podocyte injury by releasing ROS.In summary,our studies further defined the role of MDSCs in LN,that MDSCs promote kidney injury in lupus nephritis by inducing podocyte injury,and it is the first time to report that MDSCs can promote podocyte injury by releasing ROS.Our study found a theoretical basis for the treatment of LN,and provided a new way to explore the treatment strategy of LN.