Role of Myeloid-Derived Suppressor Cells in Glucocorticoid-Mediated Amelioration of FSGS

Abstract

The mechanism by which glucocorticoids alleviate renal inflammatory disorders remains incompletely understood. Here, we report that the efficacy of glucocorticoids in ameliorating FSGS depends on the capacity to expand myeloid-derived suppressor cells (MDSCs). After glucocorticoid treatment, the frequency of CD11b and kidney also increased after glucocorticoid treatment. The induced MDSCs from glucocorticoid-treated mice strongly suppressed T cells, dendritic cells, and macrophages but induced regulatory T cells in spleen, KDLNs, and kidney. Moreover, glucocorticoid treatment suppressed doxorubicin-induced T cell proliferation, dendritic cell and macrophage infiltration, and proinflammatory cytokine production, whereas this protective effect was largely abolished by depleting MDSCs using anti-Gr-1 antibody. Finally, the adoptive transfer of induced MDSCs into the doxorubicin-treated mice not only confirmed the protective role of MDSCs in doxorubicin-induced renal injury but also showed that the transferred MDSCs rapidly migrated into the lymphocyte-accumulating organs, such as the spleen and KDLNs, where they suppressed T cell proliferation. Taken together, these results demonstrate that glucocorticoid treatment ameliorates FSGS by expanding functional MDSCs and that this rapid elevation of MDSCs in peripheral blood may serve as an indicator for predicting the efficacy of glucocorticoid treatment.

Focal Segmental Glomerulosclerosis

“…The mechanism by which glucocorticoids affect podocytes are poorly understood; these agents are known to have direct effects on cultured podocytes (132). Recently, it has been suggested that these agents can expand the population of myeloid-derived suppressor cells that downregulate T cell function (133). Reliable and validated biomarkers of steroid responsiveness would be valuable.…”

Activating transcription factor 3 in immune response and metabolic regulation

“…57 One of the mechanisms through which GC inhibits inflammation is to induce expansion of myeloid-derived suppressor cells (MDSC), which in turn suppress other immune cells. 58 Expansion of MDSC is also observed in high-fat diet-fed conditions. 57 In addition to inhibiting inflammation, GC therapy causes unwanted side effects, such as liver steatosis and hyperglycemia.…”

Open-Label Clinical Trials of Oral Pulse Dexamethasone for Adults with Idiopathic Nephrotic Syndrome

“…Glucocorticoids were introduced in the therapy for the podocytopathies largely based on empiric evidence of success, particularly for MCD. The responses to this therapy have been taken as evidence of support for an immune role in pathogenesis, and there is some evidence for this [4]. Also, dexamethasone has direct effects to podocyte phenotype in vitro, including increasing nephrin mRNA expression [20].…”

“…There are at least 2 possibilities: these agents modulate immune functions and/or have a direct effect on podocytes. A recent report suggested that in FSGS and MC, glucocorticoid sensitivity is due to an expansion of the Cd11b + HLA-DR -CD14 -CD15 + cell population; these cells are immature myeloid-derived stem cells that can suppress T cell responses [4]. This would add glucocorticoid-sensitive FSGS and MCD to the list of inflammatory and autoimmune diseases in which myeloid-derived stem cells are believed to play a role, including type 1 diabetes, multiple sclerosis, and inflammatory bowel disease [5].…”