Interferon-γ-Induced Myeloid-Derived Suppressor Cells Aggravate Kidney Ischemia-Reperfusion Injury by Regulating Innate Immune Cells

Abstract

<b><i>Objective:</i></b> Myeloid-derived suppressor cells (MDSCs) are heterogeneous cells which can suppress T-cell functionality. Herein, we evaluated the functional importance of MDSCs in the context of kidney ischemia-reperfusion injury (IRI) and explored their ability to regulate innate and adaptive immune cell function in this context. <b><i>Methods:</i></b> The differentiation of MDSCs was induced in vitro by treating cells with GM-CSF and interferon (IFN)-γ. In a murine model of renal IRI, serum creatinine and blood urea nitrogen values were measured to monitor kidney function, while histopathological and immunohistochemical approaches were used to assess kidney injury severity. In addition, flow cytometry was employed to assess the phenotypes and apoptosis of kidney cells in these mice. <b><i>Results:</i></b> MDSCs induced by treatment with GM-CSF + IFN-γ could suppress T-cell functionality in vitro<i>.</i> The adoptive transfer of these MDSCs into an IRI mouse model system enhanced kidney damage and impaired renal function following the recruitment of these cells to renal tissues in these mice. Following such adoptive transfer, the relative frequency of MDSCs with a CD11b<sup>+</sup>Ly6G<sup>−</sup>Ly6C<sup>high</sup> monocytic-MDSC phenotype decreased, whereas cells with a CD11b<sup>+</sup>Ly6G<sup>+</sup>Ly6C<sup>low</sup> polymorphonuclear-MDSC phenotype become more prevalent within kidney tissues following IRI. Adoptive transfer also coincided with increased frequencies of macrophages and dendritic cells (DCs) in the kidney tissues. This suggested that M-MDSCs contributed to early-stage renal IRI damage by differentiating into these deleterious cell types. However, MDSC-induced suppression of CD4<sup>+</sup> and CD8<sup>+</sup> T-cell infiltration was not sufficient to prevent the deterioration of renal function in these mice. <b><i>Conclusions:</i></b> Herein, we successfully developed a protocol wherein MDSCs were differentiated in vitro through combination GM-CSF/IFN-γ treatment. When these MDSCs were subsequently adoptively transferred into a murine model of renal IRI, they aggravated kidney damage, likely owing to the differentiation of M-MDSCs into deleterious macrophages and DCs.

MerTK-dependent efferocytosis by monocytic-MDSCs mediates resolution of post-lung transplant injury

“…While research surrounding the role of MDSCs in lung IRI is relatively unexplored, previous studies in other organ transplant models has investigated their relative contribution. A study of renal IRI found that depletion of both MDSC subsets via GR-1 antibody led to injury improvement and adoptive transfer of a pan population of MDSCs (including both G- and M-MDSC subsets) led to worsening of renal IRI (34). These results similarly support our own data where adoptive transfer of G-MDSCs provided no protection in lung IRI (data not shown).…”

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

“…In murine kidney transplant models, MDSC have been found to aggravate IRI. These findings may be explained by the differentiation of M-MDSC into harmful macrophages and dendritic cells ( 66 ). However, the immunosuppressive effects that MDSC exert on adaptive CD4 + and CD8 + T cells were not sufficient to prevent an impairment of renal function.…”