Role Of Myeloid Derived Suppressor Cells In Glucocorticoid-Mediated Amelioration Of Focal Segmental Glomerulosclerosis

Glucocorticoids(GC)have been widely used for glomerulonephritis treatment.The mechanisms by which GC alleviates renal inflammatory disorders,however,remains incompletely understood.Here we report that the efficacy of GC in ameliorating focal segmental glomerulosclerosis(FSGS)is dependent of its capacity to expand myeloid derived suppressor cells(MDSCs).We found uncommonly accumulating of immune suppressive CD11b~+HLA-DR-CD14-CD15~+ and CD11b~+HLA-DR-CD14~+CD33~+cells in FSGS patient peripheral blood.For FSGS patients sensitive to GC treatment,the frequencies of CD11b~+HLA-DR-CD14-CD15~+ and CD11b~+HLA-DR-CD14~+CD33~+cells in peripheral blood were rapidly increased following GC treatment.In contrast,for FSGS patients insensitive to GC,the frequencies of CD11b~+HLA-DR-CD14-CD15~+ and CD11b~+HLA-DR-CD14~+CD33~+cells remained unchanged.Furthermore,we observed CD11b~+HLA-DR-CD14-CD15~+ and CD11b~+HLA-DR-CD14~+CD33~+ cells accumulating in mouse blood,spleen and bone marrow through mice Modeling,and the expanding immune suppressive cells are proved to be strongly inhibiting T cell proliferation and down-regulating cytokines level in peripheral blood After administration of GC to Adriamycin treated mice,we observed visible renal damage alleviation,accompany with an further increase of MDSC frequency in mouse blood,spleen and bone marrow,and increase cytokines level in mouse blood.These indicate that immune suppressive CD11b~+HLA-DR-CD14-CD15~+ and CD11b~+HLA-DR-CD14~+CD33~+ cells may involve in mouse initial resistance against renal injury,and GC alleviates renal damage is related to MDSC.In support of these suggestions,we managed MDSC depletion in mice,and found that GC treatment suppressed ADR-induced T cell proliferation and attenuated renal injury,whereas this effect was abolished by depleting MDSCs.Finally,adoptive transfer of MDSCs into ADR-treated mice showed that MDSCs migrated into the spleen where they suppressed the T cell proliferation,and that depletion of MDSCs aggravated ADR-induced inflammation and renal injury.Taken together,our results demonstrate that GC treatment ameliorates FSGS through expanding functional MDSCs and that elevation of MDSC level in blood may serve as an indicator for predicting the efficacy of GC treatment.