Inhibition of mitophagy drives macrophage activation and antibacterial defense during sepsis
Danish Patoli, … , Laurent Lagrost, Charles Thomas
Danish Patoli, … , Laurent Lagrost, Charles Thomas
Published August 6, 2020
Citation Information: J Clin Invest. 2020;130(11):5858-5874. https://doi.org/10.1172/JCI130996.
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Research Article Inflammation Metabolism

Inhibition of mitophagy drives macrophage activation and antibacterial 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 IFN-γ inhibited 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 triggered classical macrophage activation in a mitochondrial ROS–dependent manner. In a murine model of polymicrobial infection (cecal ligature and puncture), adoptive transfer of Pink1-deficient bone marrow or pharmacological inhibition of mitophagy promoted macrophage activation, which favored bactericidal clearance and led to a better survival rate. Reciprocally, mitochondrial uncouplers that promote mitophagy reversed LPS/IFN-γ–mediated activation of macrophages and led to immunoparalysis with impaired bacterial clearance and lowered survival. In critically ill patients, we showed that mitophagy was inhibited in blood monocytes of patients with sepsis as compared with nonseptic 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.

Authors

Danish Patoli, Franck Mignotte, Valérie Deckert, Alois Dusuel, Adélie Dumont, Aurélie Rieu, Antoine Jalil, Kevin Van Dongen, Thibaut Bourgeois, Thomas Gautier, Charlène Magnani, Naig Le Guern, Stéphane Mandard, Jean Bastin, Fatima Djouadi, Christine Schaeffer, Nina Guillaumot, Michel Narce, Maxime Nguyen, Julien Guy, Auguste Dargent, Jean-Pierre Quenot, Mickaël Rialland, David Masson, Johan Auwerx, Laurent Lagrost, Charles Thomas

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Figure 4

Polymicrobial infection and endotoxemia trigger the early inhibition of mitophagy in myeloid cells in a STAT1-dependent manner.

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Polymicrobial infection and endotoxemia trigger the early inhibition of ...
(A and B) Flow cytometry assessment of CD64hi Mitotrackerhi peritoneal macrophage subpopulation and mitochondrial density in blood monocytes of stat1+/+ or stat1–/– mice after (A) sham or CLP surgery (n = 6–7 sham; n = 5–7 CLP) or (B) i.p. injection of saline (sal.) or LPS (0.5 mg/kg, 24 hours) (n = 5–7 sal.; n = 5–7 LPS). (C and D) Flow cytometry assessment of mitochondrial density in (C) stat1+/+ or stat1–/– BMDMs or in (D) raw 264.7 macrophages targeted with control (CTL) or stat1 siRNA and then exposed to vehicle or LPS/IFN-γ for 24 hours. (E and F) Flow cytometry assessment of (E) mitochondrial ROS production and (F) Δψm in raw 264.7 macrophages targeted with CTL or stat1 siRNA and then exposed to vehicle or LPS/IFN-γ for 24 hours. (G) Oxygen consumption profile measured with Seahorse XFe96 analyzer on stat1+/+ or stat1–/– BMDMs exposed to vehicle or LPS/IFN-γ for 6 hours (n = 6–8 per condition). Graphs with plots represent mean plus individual values; bar graphs represent mean ± SEM with overlaid individual values; #P < 0.05, ##P < 0.01, ###P < 0.001 determined by ANOVA corrected for multiple comparisons. Veh, vehicle.