Abstract
Immune suppression heightens the risk for fungal infections, but the mechanisms that result in clinical disease are poorly understood. Here we demonstrate that macrophage ferroptosis, an iron-dependent form of regulated cell death, inhibits Aspergillus fumigatus ( Af ) killing. In a mouse tracheal transplant model of Af infection, we observed an increase in macrophage lipid peroxidation, a decreased expression of negative ferroptosis regulators Gpx4 and Slc7a11 , and an increase in positive regulators Ptgs2 and Nox2 , relative to syntransplants. Depletion of macrophages in transplant recipients decreased Af invasion. In vitro , iron overload reduced macrophage viability and decreased their capability to kill Af spores, through a decrease in lysosomal acidification and lysosomal loss. Treatment with ferrostatin-1, a ferroptosis inhibitor, and deferasirox (an iron chelator) restored Af killing. Ferroptotic alveolar macrophages isolated from lung transplant patients also showed a decreased ability to kill Af spores and the patients' bronchoalveolar lavage was characterized by higher iron levels and markers of ferroptotic stress compared to non-lung transplants. These characteristics were strongly correlated with a clinical history of fungal infections, independent of immune suppressive medications. Our findings indicate that macrophage ferroptosis augments the risk of invasive aspergillosis, representing a novel mechanism for host immune dysfunction.