DOI: 10.1161/str.55.suppl_1.tmp83 ISSN: 0039-2499

Abstract TMP83: Macrophage Metabolic Reprograming to Face Ferroptosis After ICH

Gael Bories, Jonathan DeLong, Lauren H Sansing
  • Advanced and Specialized Nursing
  • Cardiology and Cardiovascular Medicine
  • Neurology (clinical)

Intracerebral Hemorrhage (ICH) is a destructive neurovascular disease with no efficient treatment. Trapped Red Blood Cells (RBCs) in the brain lyse releasing toxic heme from hemoglobin. Heme, a lipophilic molecule with iron, triggers severe oxidative stress, particularly to lipid-rich cell plasma membranes (PM), causing cell death via ferroptosis. Macrophages are specialized in hematoma phagocytosis; their survival determines hematoma detoxification in the brain.

Using in vitro murine macrophage cultures treated with heme, we noted heme induced cell death (Fig 1A), along with heightened oxidized fatty acids (FAs), a marker of ferroptosis (Fig 1B). Heme-triggered cell death was countered by the ferroptosis inhibitors ferrostatin-1 (Fer-1), NAC, β-ME and Deferoxamine (DFO) (Fig 1C-F), which confirm that heme induces ferroptosis in macrophages.

Macrophages may shift metabolism to the Pentose Phosphate Pathway (PPP) in the presence of heme to promotes NADPH synthesis, vital for heme degradation and oxidation defense. Dehydroisoandrosterone (DHEA), a potent PPP inhibitor, worsened heme-induced ferroptosis (Fig 1 G&H). This underscores the PPP's vital role against heme-driven ferroptosis.

Ferroptosis involves PM oxidation and loss of integrity, causing cell death. Heme induced rapid extracellular ATP release (Fig I). Lysosomes contain abundant ATP, thus we hypothesized that ATP release triggers by heme is the result of PM repair by lysosomal exocytosis/endocytosis. Using metabolomics, we found that heme induced accumulation of membrane components like phospholipids, sphingolipids, and cholesterol (Fig J-L), all which require NADPH for synthesis. This suggests PPP aids NADPH production, aiding lysosomal synthesis for PM repair. Overall, the findings support a critical role for the PPP in macrophage resistance to ferroptosis in the presence of heme and suggest a possible new therapeutic target for macrophage survival after ICH.

More from our Archive