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Inhibition of mitophagy drives macrophage activation and anti-bacterial defense during sepsis

Abstract : Mitochondria have emerged as key actors of innate and adaptive immunity. Mitophagy has a pivotal role in cell homeostasis but its contribution to macrophage functions and host defense remains to be delineated. Here we showed that lipopolysaccharide (LPS) in combination with IFNγ, inhibits PINK1-dependent mitophagy in macrophages through a STAT1-dependent activation of the inflammatory caspases 1 and 11. In addition, we demonstrated that the inhibition of mitophagy triggers classical macrophage activation in a mitochondrial ROS-dependent manner. In a murine model of polymicrobial infection (cecal ligature and puncture, CLP), adoptive transfer of Pink1-deficient bone marrow or pharmacological inhibition of mitophagy promoted macrophage activation which favored bactericidal clearance and lead to a better survival. Reciprocally, mitochondrial uncouplers, that promote mitophagy, reverse LPS/IFNγ-mediated activation of macrophages and lead to immuno-paralysis with impaired bacterial clearance and lowered survival. In critically ill patients, we showed that mitophagy is inhibited in blood monocytes of patients with sepsis as compared to non-septic patients. Overall, this work demonstrates that the inhibition of mitophagy is a physiological mechanism that contributes to the activation of myeloid cells and improves the outcome of sepsis.
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Contributor : Stéphane Mandard Connect in order to contact the contributor
Submitted on : Monday, August 31, 2020 - 10:02:00 PM
Last modification on : Wednesday, September 28, 2022 - 4:20:12 PM

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Danish Patoli, Franck Mignotte, Valérie Deckert, Alois Dusuel, Adélie Dumont, et al.. Inhibition of mitophagy drives macrophage activation and anti-bacterial defense during sepsis. Journal of Clinical Investigation, American Society for Clinical Investigation, 2020, 130996, Online ahead of print. ⟨10.1172/JCI130996⟩. ⟨inserm-02926629⟩



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