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

Area of Science:

• Immunology
• Nephrology
• Cardiovascular Science

Background:

• Cyclosporine A (CsA) is an immunosuppressant that causes hypertension and organ damage.
• CsA's impact on myeloid-derived suppressor cells (MDSCs), crucial regulators of immune responses, remains unclear.
• Regulatory T cells are known to be decreased by CsA, contributing to hypertension.

Purpose of the Study:

• To investigate if augmenting MDSCs can mitigate CsA-induced hypertension and organ damage.
• To determine if CsA treatment reduces MDSC levels in mice.

Main Methods:

• Mice were treated with CsA and/or interleukin-33 (to increase MDSCs) or received adoptive transfer of MDSCs.
• Vascular and renal function, blood pressure, and cellular/molecular markers of injury and inflammation were assessed.
• Isolated aortas and kidneys were analyzed for relaxation responses and inflammation.
• CsA's effect on MDSC numbers and calcineurin signaling was examined.

Main Results:

• Interleukin-33 treatment completely prevented CsA-induced hypertension and vascular/renal toxicity.
• Adoptive transfer of MDSCs dose-dependently reduced blood pressure and injury in CsA-treated mice.
• MDSCs prevented CsA-induced vascular dysfunction, inflammation, and fibronectin increase in endothelial cells.
• CsA reduced MDSC numbers by inhibiting calcineurin and cell proliferation.

Conclusions:

• Augmenting MDSCs effectively ameliorates CsA-induced hypertension and cardiovascular/renal toxicity.
• CsA reduces MDSC levels through calcineurin inhibition, highlighting a potential therapeutic target.
• MDSCs represent a promising strategy to mitigate the adverse effects of CsA therapy.