Granulocyte Colony-Stimulating Factor Attenuates Renal Ischemia-Reperfusion Injury by Inducing Myeloid-Derived Suppressor Cells

Abstract

BackgroundGranulocyte colony-stimulating factor (G-CSF) can increase populations of myeloid-derived suppressor cells, innate immune suppressors that play an immunoregulatory role in antitumor immunity. However, the roles of myeloid-derived suppressor cells and G-CSF in renal ischemia-reperfusion injury remain unclear.MethodsWe used mouse models of ischemia-reperfusion injury to investigate whether G-CSF can attenuate renal injury by increasing infiltration of myeloid-derived suppressor cells into kidney tissue.ResultsG-CSF treatment before ischemia-reperfusion injury subsequently attenuated acute renal dysfunction, tissue injury, and tubular apoptosis. Additionally, G-CSF treatment suppressed renal infiltration of macrophages and T cells as well as renal levels of IL-6, MCP-1, IL-12, TNF-α, and IFN-γ, but it increased levels of IL-10, arginase-1, and reactive oxygen species. Moreover, administering G-CSF after ischemia-reperfusion injury improved the recovery of renal function and attenuated renal fibrosis on day 28. G-CSF treatment increased renal infiltration of myeloid-derived suppressor cells (F4/80−CD11b+Gr-1int), especially the granulocytic myeloid-derived suppressor cell population (CD11b+Ly6GintLy6Clow); splenic F4/80−CD11b+Gr-1+ cells sorted from G-CSF–treated mice displayed higher levels of arginase-1, IL-10, and reactive oxygen species relative to those from control mice. Furthermore, these splenic cells effectively suppressed in vitro T cell activation mainly through arginase-1 and reactive oxygen species, and their adoptive transfer attenuated renal injury. Combined treatment with anti–Gr-1 and G-CSF showed better renoprotective effects than G-CSF alone, whereas preferential depletion of myeloid-derived suppressor cells by pep-G3 or gemcitabine abrogated the beneficial effects of G-CSF against renal injury.ConclusionsG-CSF induced renal myeloid-derived suppressor cells, thereby attenuating acute renal injury and chronic renal fibrosis after ischemia-reperfusion injury. These results suggest therapeutic potential of myeloid-derived suppressor cells and G-CSF in renal ischemia-reperfusion injury.

Multiplex Bead Array Assay of a Panel of Circulating Cytokines and Growth Factors in Patients with Albuminuric and Non-Albuminuric Diabetic Kidney Disease

“…The treatment with G-CSF increased a renal infiltration of myeloid-derived suppressor cells [48]. Nevertheless, G-CSF showed renal protective activity in a model of kidney ischemia-reperfusion [48] and diabetic nephropathy [49,50]. The data is inconsistent with our results, indicating an increase in the level of G-CFS in patients with reduced renal function, especially those with NA-CKD.…”

“…Renal ischemia-reperfusion induces G-CSF gene expression in thick ascending limb cells and increased serum concentration of G-CSF [47]. The treatment with G-CSF increased a renal infiltration of myeloid-derived suppressor cells [48]. Nevertheless, G-CSF showed renal protective activity in a model of kidney ischemia-reperfusion [48] and diabetic nephropathy [49,50].…”

Review: Ischemia Reperfusion Injury—A Translational Perspective in Organ Transplantation

“…This is consistent with a recent study that reported the natural expansion of MDSCs following heart allograft transplantation in mice that favor graft survival prolongation [106]. In the context of renal IRI, a recent study by Yan et al [107] evaluated the role of MDSCs using an experimental model and found that after induction by granulocyte colony-stimulating factor (G-CSF), MDSC secrete arginase-1 (ARG-1), which prevents T cell proliferation and potent immune responses. In this model, while MDSC would appear as protective, other studies have reported that MDSCs are mobilized by CRP to further exacerbate renal damage in IRI [108].…”

Androgen-Influenced Polarization of Activin A-Producing Macrophages Accompanies Post-pyelonephritic Renal Scarring

“…M1 polarization occurs via stimulation with several pro-inflammatory signals (e.g., LPS and IFNγ, with ensuing TNFα, and IL-6 production) ( 15 – 23 ), as are normally elicited early after bacterial infection of the urinary tract ( 104 – 106 ). M2 macrophages are sensitive to a variety of Th2 cytokines, including CXCL1, G-CSF and IL-10 ( 27 , 31 – 33 ). The whole-kidney cytokine profiles following UPEC infection aligned with the macrophage polarization states we observed, with androgenized mice exhibiting suppressed IFNγ and unaltered TNFα, accompanied by increased CXCL1 and G-CSF.…”

“…These M1 cells further secrete proinflammatory cytokines and chemokines, exert phagocytic activity, and induce neutrophil apoptosis (25)(26)(27)(28)(29)(30). Reduction of local DAMP and PAMP quantities, along with an increase in neutrophil debris, and accumulation of T H 2 cytokines, including cytokines such as CXCL1, G-CSF, and IL-10 (27,(31)(32)(33), subsequently encourages these M1 macrophages to polarize toward alternatively activated M2 macrophages (34)(35)(36)(37)(38). M2a macrophages are activated by IL-4 and IL-13, and are considered pro-fibrotic (39)(40)(41)(42).…”