Myeloid-Derived Suppressor Cells Alleviate Renal Fibrosis Progression via Regulation of CCL5-CCR5 Axis

Abstract

BackgroundRenal fibrosis is inevitable in all progressive chronic kidney diseases (CKDs) and represents a serious public health problem. Immune factors contribute to the progression of renal fibrosis. Thus, it is very possible that immunosuppression cells, such as myeloid-derived suppressor cells (MDSCs), could bring benefits to renal fibrosis. Herein, this study investigated the antifibrotic and reno-protective effect of MDSCs and the possible mechanisms.MethodsMurine and cell models of unilateral ureter obstruction (UUO) renal fibrosis were used. Bone marrow-induced MDSCs and granulocyte–macrophage colony-stimulating factor (GM-CSF) were pretreated before surgery. Kidney weight, pathological injury, extracellular matrix deposition, and epithelial–mesenchymal transition progression were examined. Transforming growth factor (TGF)-β1)/Smad/Snail signaling pathway involvement was investigated through Western blotting and quantitative PCR (qPCR). Accumulation of MDSC, CD4+ T cell, regulatory T (Treg), and T helper 1 (TH1) cell accumulation, and CCL5 and CCR5 expression level in MDSCs and non-MDSCs were evaluated using flow cytometry.ResultsIn vitro- and in vivo-induced MDSCs significantly ameliorated UUO-induced tubulointerstitial fibrosis, inhibited the TGF-β1/Smad/Snail signaling pathway, and enhanced MDSC and Treg infiltration in the kidney while downregulating the TH1 cells. Both in vitro and in vivo experiments confirmed CCL5 elevation in the two MDSC-treated groups.ConclusionIn vitro- and in vivo-induced MDSCs alleviated renal fibrosis similarly through promoting the CCL5–CCR5 axis interaction and TGF-β1/Smad/Snail signaling pathway inhibition. Our results indicate an alternative treatment for renal fibrosis.

Revealing Potential Diagnostic Gene Biomarkers Associated with Immune Infiltration in Patients with Renal Fibrosis Based on Machine Learning Analysis

“…The potential function of the above genes has been reported in renal fibrosis. For instance, the CCL5-CCR5 axis and the TGF-1/Smad/Snail signaling pathways were inhibited by inducing myeloid-derived suppressor cells in vitro and in vivo, and both methods reduced kidney fibrosis [ 30 ]. Smad4 deacetylation and inhibition of MMP7 expression by upregulated SIRT1 in RSV reduced kidney damage and fibrosis, which was related to the upregulation of SIRT1 by RSV [ 31 ].…”

Innate immunity in diabetic nephropathy: Pathogenic mechanisms and therapeutic targets

“…TGF‐β1 binds to its receptor, prompting phosphorylation of SMAD2 and SMAD3, forming the SMAD complex by binding to SMAD4, driving Snail expression and promoting epithelial‐mesenchymal transition and fibrosis 154–156 . Although it is unclear whether MDSCs ameliorate fibrosis of DN by this way, in unilateral ureter obstruction mice model, bone marrow‐induced MDSCs significantly inhibit the TGF‐β1/SMAD/Snail pathway and thus alleviate renal fibrosis progression 157 …”

“…[154][155][156] Although it is unclear whether MDSCs ameliorate fibrosis of DN by this way, in unilateral ureter obstruction mice model, bone marrow-induced MDSCs significantly inhibit the TGF-β1/SMAD/Snail pathway and thus alleviate renal fibrosis progression. 157…”

Aging Affects the Role of Myeloid-Derived Suppressor Cells in Alloimmunity

“…In contrast, increased renal infiltration of MDSC upon granulocyte colony-stimulating factor (G-CSF) administration improved renal function after IRI and attenuated acute tissue injury as well as chronic renal fibrosis ( 68 , 69 ). In addition, further mechanistic studies have shown that renal fibrosis can be alleviated by MDSC through CCL5-CCR-5 axis regulation and TGF-β1/Smad/Snail signaling pathway inhibition ( 70 ).…”