Ferroptotic cell death and TLR4/Trif signaling initiate neutrophil recruitment after heart transplantation

Non-apoptotic forms of cell death can trigger sterile inflammation through the release of danger-associated molecular patterns, which are recognized by innate immune receptors. However, despite years of investigation the mechanisms which initiate inflammatory responses after heart transplantation remain elusive. Here, we demonstrate that ferrostatin-1 (Fer-1), a specific inhibitor of ferroptosis, decreases the level of pro-ferroptotic hydroperoxy-arachidonoyl-phosphatidylethanolamine, reduces cardiomyocyte cell death and blocks neutrophil recruitment following heart transplantation. Inhibition of necroptosis had no effect on neutrophil trafficking in cardiac grafts. We extend these observations to a model of…

• BW
  Burroughs Wellcome Fund

  Awards: 1014,82, 1014782
• FF
  Foundation for Barnes-Jewish Hospital

  Awards: 63110, 1I01BX002730, R01HL094601
• NI
  National Institutes of Health

  Awards: P01AI116501, R01 HL138466, DK52574, R01HL094601, P30 DK52574, HL139714, R01 HL139714, 1I01BX002730, HL138466, K08 HL123519