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J Leukoc Biol. 2018 Feb;103(2):175-183. doi: 10.1189/jlb.3HI0517-173R. Epub 2017 Dec 28.

Frontline Science: Macrophage-derived exosomes promote neutrophil necroptosis following hemorrhagic shock.

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Department of Anesthesiology, Shanghai Xinhua Hospital, Jiaotong University School of Medicine, Shanghai, China.
Department of Surgery, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA.
Research and Development, Veterans Affairs Pittsburgh Healthcare System, Pittsburgh, Pennsylvania, USA.
University of Pittsburgh School of Arts and Science, Pittsburgh, Pennsylvania, USA.
McGowan Institute for Regenerative Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania, USA.


Hemorrhagic shock (HS) renders patients susceptible to development of systemic inflammatory response syndrome (SIRS) and multiple organ dysfunction syndrome (MODS) through mechanisms that are, as yet, unclear. Cell necroptosis, a form of regulated inflammatory cell death, is one of the mechanisms that controls cell release of inflammatory mediators from innate immune cells, such as polymorphonuclear neutrophils (PMNs), and critically regulates the progress of inflammation. In this study, we investigated the mechanisms of alveolar macrophage (AMϕ) effects on PMN necroptosis following HS. With the use of in vivo and ex vivo HS models, we reveal a novel function of shock-activated AMϕ in promoting PMN necroptosis. We demonstrate that exosomes released from HS-activated AMϕ induce mainly NADPH oxidase-derived reactive oxygen species (ROS) production inside PMNs and subsequent promotion of necroptosis. These findings explore a previously unidentified pathway of AMϕ-PMN cross-talk, which causes enhanced PMN necroptosis and subsequent exaggerated post-HS lung inflammation. The targeting of this PMN death pathway may serve as a new therapeutic strategy for treatment of post-HS SIRS.


cell death; cell-cell interaction; extracellular vesicles

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