Loss of mTORC2 Activity in Neutrophils Impairs Fusion of Granules and Affects Cellular Metabolism Favoring Increased Bacterial Burden in Sepsis

J Immunol. 2021 Jul 15;207(2):626-639. doi: 10.4049/jimmunol.2000573. Epub 2021 Jul 14.

Abstract

Sepsis is a complex infectious syndrome in which neutrophil participation is crucial for patient survival. Neutrophils quickly sense and eliminate the pathogen by using different effector mechanisms controlled by metabolic processes. The mammalian target of rapamycin (mTOR) pathway is an important route for metabolic regulation, and its role in neutrophil metabolism has not been fully understood yet, especially the importance of mTOR complex 2 (mTORC2) in the neutrophil effector functions. In this study, we observed that the loss of Rictor (mTORC2 scaffold protein) in primary mouse-derived neutrophils affects their chemotaxis by fMLF and their microbial killing capacity, but not the phagocytic capacity. We found that the microbicidal capacity was impaired in Rictor-deleted neutrophils because of an improper fusion of granules, reducing the hypochlorous acid production. The loss of Rictor also led to metabolic alterations in isolated neutrophils, increasing aerobic glycolysis. Finally, myeloid-Rictor-deleted mice (LysMRic Δ/Δ) also showed an impairment of the microbicidal capacity, increasing the bacterial burden in the Escherichia coli sepsis model. Overall, our results highlight the importance of proper mTORC2 activation for neutrophil effector functions and metabolism during sepsis.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Chemotaxis / physiology
  • Escherichia coli / metabolism
  • Female
  • Glycolysis / physiology
  • Humans
  • Hypochlorous Acid / metabolism
  • Mechanistic Target of Rapamycin Complex 2 / metabolism*
  • Mice
  • Mice, Inbred C57BL
  • Neutrophils / metabolism*
  • Phagocytosis / physiology
  • Sepsis / metabolism*
  • Sepsis / microbiology*
  • Signal Transduction / physiology

Substances

  • Hypochlorous Acid
  • Mechanistic Target of Rapamycin Complex 2