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Macrophage ferroptosis inhibits Aspergillus conidial killing in lung transplantation
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.
Insights
Macrophage ferroptosis, a cell death process, impairs the immune system's ability to fight fungal infections like aspergillosis. Inhibiting this process can restore immune function and fungal killing capacity.
Area of Science:
- Immunology
- Cell Biology
- Infectious Diseases
Background:
- Immune suppression increases susceptibility to fungal infections, but underlying mechanisms remain unclear.
- Macrophage ferroptosis, a regulated cell death pathway dependent on iron, is implicated in immune dysfunction.
Purpose of the Study:
- To investigate the role of macrophage ferroptosis in inhibiting the killing of *Aspergillus fumigatus* (Af).
- To explore the clinical relevance of macrophage ferroptosis in invasive aspergillosis.
Main Methods:
- Utilized a mouse tracheal transplant model of Af infection.
- Analyzed macrophage ferroptosis markers, including lipid peroxidation and gene expression (Gpx4, Slc7a11, Ptgs2, Nox2).
- Conducted *in vitro* experiments with iron overload and ferroptosis inhibitors (ferrostatin-1, deferasirox).
- Examined alveolar macrophages and bronchoalveolar lavage fluid from lung transplant patients.
Main Results:
- Macrophage ferroptosis was increased in the mouse model, correlating with reduced Af killing.
- Iron overload impaired macrophage viability and Af-killing capacity *in vitro*.
- Ferrostatin-1 and deferasirox treatment restored Af killing.
- Ferroptotic macrophages from lung transplant patients showed reduced Af-killing ability, linked to higher iron levels and ferroptotic stress markers.
Conclusions:
- Macrophage ferroptosis inhibits the immune response against *Aspergillus fumigatus*.
- This ferroptosis-driven immune dysfunction augments the risk of invasive aspergillosis.
- Macrophage ferroptosis represents a novel mechanism contributing to host immune dysfunction in fungal infections.
