Administration of cytokine-induced myeloid-derived suppressor cells ameliorates renal fibrosis in diabetic mice.
BACKGROUND
Diabetes 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.


METHODS
Cytokine-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.


RESULTS
MDSCs 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.


CONCLUSIONS
The application of cytokine-induced MDSCs provides a promising treatment for renal fibrosis and the prevention of diabetic nephropathy.
['Hsieh|Ching-Chuan|CC|0000-0001-8554-328X', 'Lin|Chun-Liang|CL|', 'He|Jie-Teng|JT|', 'Chiang|Meihua|M|', 'Wang|Yuhsiu|Y|', 'Tsai|Yu-Chin|YC|', 'Hung|Chien-Hui|CH|', 'Chang|Pey-Jium|PJ|']
D000818:Animals D002478:Cells, Cultured D016207:Cytokines D003921:Diabetes Mellitus, Experimental D005355:Fibrosis D016178:Granulocyte-Macrophage Colony-Stimulating Factor D007150:Immunohistochemistry D007672:Kidney Cortex D008297:Male D051379:Mice D008807:Mice, Inbred BALB C D008810:Mice, Inbred C57BL D018613:Microscopy, Confocal D022423:Myeloid Cells D000072737:Myeloid-Derived Suppressor Cells D020133:Reverse Transcriptase Polymerase Chain Reaction
Myeloid-derived suppressor cells Fibronectin Immunotherapy Diabetic nephropathy