Journal
JOURNAL OF CLINICAL INVESTIGATION
Volume 129, Issue 6, Pages 2293-2304Publisher
AMER SOC CLINICAL INVESTIGATION INC
DOI: 10.1172/JCI126428
Keywords
-
Categories
Funding
- NIH [P30 DK52574, P01AI116501, R01HL094601, R01 HL138466, R01 HL139714, K08 HL123519]
- Veterans Administration Merit Review grant [1I01BX002730]
- Foundation for Barnes-Jewish Hospital
- Burroughs Wellcome Fund [1014782]
Ask authors/readers for more resources
Nonapoptotic forms of cell death can trigger sterile inflammation through the release of damage-associated molecular patterns, which are recognized by innate immune receptors. However, despite years of investigation, the mechanisms that initiate inflammatory responses after heart transplantation remain elusive. Here, we demonstrate that ferrostatin-1 (Fer-1), a specific inhibitor of ferroptosis, decreases the levels 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 coronary artery ligation-induced myocardial ischemia reperfusion injury (IRI), in which inhibition of ferroptosis resulted in reduced infarct size, improved left ventricular (LV) systolic function, and reduced LV remodeling. Using intravital imaging of cardiac transplants, we show that ferroptosis orchestrates neutrophil recruitment to injured myocardium by promoting adhesion of neutrophils to coronary vascular endothelial cells through a TLR4/Trif/type I IFN signaling pathway. Thus, we have discovered that inflammatory responses after cardiac transplantation are initiated through ferroptotic cell death and TLR4/Trif-dependent signaling in graft endothelial cells. These findings provide a platform for the development of therapeutic strategies for heart transplant recipients and patients who are vulnerable to IRI following restoration of coronary blood flow.
Authors
I am an author on this paper
Click your name to claim this paper and add it to your profile.
Reviews
Recommended
No Data Available