Abstract
BackgroundDiabetes is a proinflammatory state. Fibrosis of the renal glomerulus is the most common cause of end-stage renal disease. Glomerulosclerosis is caused by the accumulation of extracellular matrix (ECM) proteins in the mesangial interstitial space. Mesangial cells are unique stromal cells in the renal glomerulus that form the vascular pole of the renal corpuscle along with the mesangial matrix. Myeloid-derived suppressor cells (MDSCs) are heterogeneous immature myeloid cells that rapidly expand to regulate host immunity during inflammation, infection, and cancer. High concentrations of granulocyte–macrophage colony-stimulating factor (GM-CSF) alone or in combination with other molecules represent the most common ex-vivo protocol for differentiating MDSCs from bone marrow or from peripheral blood mononuclear cells. In this study, we analyzed and characterized the functions of MDSCs under the influence of mouse mesangial cells (MMCs) in a hyperglycemic environment and investigated whether cytokine-induced MDSCs ameliorated renal glomerulosclerosis in diabetic mice.MethodsCytokine-induced MDSCs were propagated from bone marrow cells cultured with mouse recombinant GM-CSF, IL-6, and IL-1β. Diabetic mice were induced with streptozotocin (STZ) and maintained at a blood glucose concentration exceeding 350 mg/dl. The ECM of the renal cortex and fibronectin expression of MMCs were analyzed through immunohistochemistry and western blotting. Arginase 1 and inducible NO synthase expressions of MDSCs were evaluated using quantitative reverse-transcriptase PCR. Cytokines released from MMCs were examined using a cytokine array assay.ResultsMDSCs in the diabetic mice were redistributed from the bone marrow into peripheral organs. An increase in fibronectin production was also observed in the renal glomerulus. MMCs in vitro produced more fibronectin and proinflammatory cytokines, such as macrophage inflammatory protein-2, RANTES, and stromal-cell-derived factor-1, under hyperglycemic conditions. The adoptive transfer of cytokine-induced MDSCs into STZ-induced mice normalized the glomerular filtration rate to reduce the kidney to body weight ratio and decrease fibronectin production in the renal glomerulus, ameliorating renal fibrosis. These results demonstrate the anti-inflammatory properties of cytokine-induced MDSCs and offer an alternative immunotherapy protocol for the management of diabetic nephropathy.ConclusionsThe application of cytokine-induced MDSCs provides a promising treatment for renal fibrosis and the prevention of diabetic nephropathy.
Highlights
Diabetes may trigger the redistribution of Myeloid-derived suppressor cells (MDSCs) from the bone marrow (BM) to peripheral organs, including the peripheral blood, spleen, and kidneys
Similar results of MDSC expansion were noted in the spleen parenchyma (Fig. 1d, upper panel), and a slight increase was observed in the renal glomerulus (Fig. 1d, upper panel, dotted circle) in the STZ-treated mice through immunofluorescence staining
The numbers of MDSCs within the spleen parenchyma and renal glomerulus in the STZ-treated mice were 2.3 and 1.75 times that of untreated mice (P < .05 and P = .183, respectively; Fig. 1d, lower panel). These results demonstrated that higher extracellular matrix (ECM) expression occurs in the renal cortex, and that MDSCs are redistributed from the BM to the peripheral organs in STZ-treated diabetic mice
Summary
Glomerulosclerosis in diabetic nephropathy is caused by accumulation of extracellular matrix (ECM) proteins in the mesangial interstitial space, resulting in fibrosis manifested by either diffuse or nodular changes [3]. Myeloid-derived suppressor cells (MDSCs) were described more than 20 years ago in patients with cancer [6,7,8], but their functional importance in the immune system has only recently been appreciated In pathological conditions, such as cancer, infectious diseases, sepsis, trauma, BM transplantation, and some autoimmune disorders, a partial block in the differentiation of immature myeloid cells results in an expansion of MDSCs [9]. Immunoregulatory activities within MDSCs include increased production of arginase I [11], inducible NO synthase (iNOS) [12], reactive oxygen species [13, 14], and anti-inflammatory cytokines [15]
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