Myeloid-Derived Suppressor Cells Ameliorate Cyclosporine A–Induced Hypertension in Mice

Abstract

The calcineurin inhibitor cyclosporine A (CsA) suppresses the immune system but promotes hypertension, vascular dysfunction, and renal damage. CsA decreases regulatory T cells and this contributes to the development of hypertension. However, CsA's effects on another important regulatory immune cell subset, myeloid-derived suppressor cells (MDSCs), is unknown. We hypothesized that augmenting MDSCs would ameliorate the CsA-induced hypertension and vascular and renal injury and dysfunction and that CsA reduces MDSCs in mice. Daily interleukin-33 treatment, which increased MDSC levels, completely prevented CsA-induced hypertension and vascular and renal toxicity. Adoptive transfer of MDSCs from control mice into CsA-treated mice after hypertension was established dose-dependently reduced blood pressure and vascular and glomerular injury. CsA treatment of aortas and kidneys isolated from control mice for 24 hours decreased relaxation responses and increased inflammation, respectively, and these effects were prevented by the presence of MDSCs. MDSCs also prevented the CsA-induced increase in fibronectin in microvascular and glomerular endothelial cells. Last, CsA dose-dependently reduced the number of MDSCs by inhibiting calcineurin and preventing cell proliferation, as other direct calcineurin signaling pathway inhibitors had the same dose-dependent effect. These data suggest that augmenting MDSCs can reduce the cardiovascular and renal toxicity and hypertension caused by CsA.

Myeloid-derived suppressor cells expand after transplantation and their augmentation increases graft survival

“…For example, anti‐thymoglobulin is known to reduce populations of MDSCs, but its primary effect was on PMN‐MDSCs, rather than on M‐MDSCs 3 . Cyclosporine is known to decrease MDSC populations, whereas rapamycin and corticosteroids are known to increase MDSC populations 36,37,40 . Accordingly, we used a model of transplant in which animals did not receive immunosuppression; all animals demonstrated expanded MDSCs and these MDSCs were suppressive of T cell responses.…”

The role of inflammation in hypertension: novel concepts

“…Shah et al demonstrated that a subpopulation of myeloid cells, myeloid-derived suppressor cells (MDSCs), limit the increase in blood and inflammation in response to three murine models of experimental hypertension [ 25 ]. In a cyclosporine-A model of hypertension, Chiasson et al found that adoptive transfer of MSDCs prevented renal and vascular inflammation and improved vascular relaxation [ 26 ]. More recently, Crowley et al demonstrated that DCs expressing A20, a ubiquitin-editing protein known to preserve immune system hemostasis, abrogates Ang II-induced elevations in blood pressures by preventing renal activated T-cell accumulation [ 20 ], demonstrating a vital role of myeloid cells in the suppression of inflammatory events during hypertensive insults.…”

The Effect of Immunosuppressive Drugs on MDSCs in Transplantation

“…Treatment of bone marrow-derived macrophages (BMDMs) with tacrolimus significantly inhibited LPS and LPS plus IFN- γ -induced IL-12p40 mRNA and protein expression [ 100 ]. After coculture with increasing concentrations of CsA for 24 h, the number of live splenic MDSCs decreased significantly in a dose-dependent manner by calcineurin inhibition [ 101 ]. In the mouse skin transplant model, a daily dose of 15–30 mg/kg of CsA can promote the accumulation of CD11b + Gr-1 + MDSCs in the graft, draining lymph nodes, spleen, peripheral blood, and bone marrow with the prolonged survival time of grafts [ 102 ].…”