Necroptosis triggers spatially restricted neutrophil-mediated vascular damage during lung ischemia reperfusion injury

Wenjun Li, Yuriko Terada, Yulia Y. Tyurina, Vladimir A. Tyurin, Amit I. Bery, Jason M. Gauthier, Ryuji Higashikubo, Alice Y. Tong, Dequan Zhou, Felix Nunez-Santana, Emilia Lecuona, Adil Hassan, Kohei Hashimoto, Davide Scozzi, Varun Puri, Ruben G. Nava, Alexander S. Krupnick, Kory J. Lavine, Andrew E. Gelman, Mark J. MillerValerian E. Kagan, Ankit Bharat, Daniel Kreisel*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

27 Scopus citations


Ischemia reperfusion injury represents a common pathological condition that is triggered by the release of endogenous ligands. While neutrophils are known to play a critical role in its pathogenesis, the tissue-specific spatiotemporal regulation of ischemia-reperfusion injury is not understood. Here, using oxidative lipidomics and intravital imaging of transplanted mouse lungs that are subjected to severe ischemia reperfusion injury, we discovered that necroptosis, a nonapoptotic form of cell death, triggers the recruitment of neutrophils. During the initial stages of inflammation, neutrophils traffic predominantly to subpleural vessels, where their aggregation is directed by chemoattractants produced by nonclassical monocytes that are spatially restricted in this vascular compartment. Subsequent neutrophilic disruption of capillaries resulting in vascular leakage is associated with impaired graft function. We found that TLR4 signaling in vascular endothelial cells and downstream NADPH oxidase 4 expression mediate the arrest of neutrophils, a step upstream of their extravasation. Neutrophil extracellular traps formed in injured lungs and their disruption with DNase prevented vascular leakage and ameliorated primary graft dysfunction. Thus, we have uncovered mechanisms that regulate the initial recruitment of neutrophils to injured lungs, which result in selective damage to subpleural pulmonary vessels and primary graft dysfunction. Our findings could lead to the development of new therapeutics that protect lungs from ischemia reperfusion injury.

Original languageEnglish (US)
Article numbere2111537119
JournalProceedings of the National Academy of Sciences of the United States of America
Issue number10
StatePublished - Mar 8 2022


  • intravital imaging
  • ischemia reperfusion injury
  • transplantation

ASJC Scopus subject areas

  • General


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