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RESEARCH PRODUCT

Mitophagy in myeloid cells : role in infection with gram-negative bacteria

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Sepsis and related organ dysfunctions remain a leading cause of mortality in intensive care units. Increasing evidences have shed light on an unexpected link between mitochondria and immune cell functions. Alterations in mitochondrial functions have been reported in peripheral blood cells in sepsis. We hypothesize here that mitophagy might impact on phagocyte functions in the context of bacterial infection. Mitophagy is a mitochondria-dedicated autophagy that governs the elimination of dysfunctional mitochondria. We demonstrated here in vivo and in vitro that macrophages exposed to Gram-negative bacteria or their cell wall component LPS display a marked inhibition of mitophagy that constitutes a protective mechanism against sepsis. LPS/IFNγ-driven macrophage activation results in early inhibition of PINK1-dependent mitophagy through a STAT1-Caspase 4/11 pathway. This inhibition of mitophagy contributes to explain the metabolic reprogramming observed in classically activated macrophages and leads to a rise in mitochondrial ROS (mROS) production. As signaling molecules, mROS lead to macrophages activation in a HIF-1α- and NF-κB-dependent manner. Furthermore, these molecules contribute to bacterial clearance in activated phagocytes. Interestingly, we demonstrated in vitro and in vivo that pharmacological modulation of mitophagy allows either mimicking or repressing the effects of LPS on macrophages polarization, cytokine release and bactericidal activity. To conclude, this work demonstrates that inhibition of mitophagy is a feature of LPS-dependent macrophage activation and a protective mechanism against Gram-negative bacteria. This study also highlights an unknown relationship between IFNγ-signaling, inflammatory caspases and mitophagy. Finally, our work point out the impact of pharmacological modulators of mitophagy on macrophage function and open new opportunities for the development of novel strategies to boost host defense