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Media type:
E-Article
Title:
Mitochondria Released by Apoptotic Cell Death Initiate Innate Immune Responses
Contributor:
Zhu, Minghua;
Barbas, Andrew S.;
Lin, Liwen;
Scheuermann, Uwe;
Bishawi, Muath;
Brennan, Todd V.
Published:
The American Association of Immunologists, 2018
Published in:
ImmunoHorizons, 2 (2018) 11, Seite 384-397
Language:
English
DOI:
10.4049/immunohorizons.1800063
ISSN:
2573-7732
Origination:
Footnote:
Description:
Abstract In solid organ transplantation, cell death arising from ischemia/reperfusion leads to the release of several damage-associated molecular patterns derived from mitochondria. Mitochondrial damage-associated molecular patterns (mtDAMPs) initiate proinflammatory responses, but it remains unknown whether the mode of cell death affects the inflammatory properties of mitochondria. Murine and human cell lines induced to selectively undergo apoptosis and necroptosis were used to examine the extracellular release of mitochondria during programmed cell death. Mitochondria purified from healthy, apoptotic, and necroptotic cells were used to stimulate macrophage inflammasome responses in vitro and neutrophil chemotaxis in vivo. Inhibition of specific mtDAMPs was performed to identify those responsible for macrophage inflammasome activation. A rat liver transplant model was used to identify apoptotic and necroptotic cell death in graft tissue following ischemia/reperfusion. Both apoptotic and necroptotic cell death occur in parallel in graft tissue. Apoptotic cells released more mitochondria than necroptotic cells. Moreover, mitochondria from apoptotic cells were significantly more inflammatory in terms of macrophage inflammasome activation and neutrophil recruitment. Inhibition of cellular synthesis of cardiolipin, a mitochondria-specific lipid and mtDAMP, significantly reduced the inflammasome-activating properties of apoptosis-derived mitochondria. Mitochondria derived from apoptotic cells are potent activators of innate immune responses, whereas mitochondria derived from healthy or necroptotic cells are significantly less inflammatory. Cardiolipin appears to be a key mtDAMP-regulating inflammasome activation by mitochondria. Methods of inhibiting apoptotic cell death in transplant grafts may be beneficial for reducing graft inflammation and transplant allosensitization.