Administration of cytokine-induced myeloid-derived suppressor cells ameliorates
renal fibrosis in diabetic mice
#MMPMID29973247
Hsieh CC
; Lin CL
; He JT
; Chiang M
; Wang Y
; Tsai YC
; Hung CH
; Chang PJ
Stem Cell Res Ther
2018[Jul]; 9
(1
): 183
PMID29973247
show ga
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-1?. 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.
free
free
free
