Mechanistic Target of Rapamycin Inhibition Extends Cellular Lifespan in Dendritic Cells by Preserving Mitochondrial Function

Abstract

TLR-mediated activation of dendritic cells (DCs) is associated with a metabolic transition in which mitochondrial oxidative phosphorylation is inhibited by endogenously synthesized NO and the cells become committed to glucose and aerobic glycolysis for survival. We show that inhibition of mechanistic target of rapamycin (mTOR) extends the lifespan of TLR-activated DCs by inhibiting the induction of NO production, thereby allowing the cells to continue to use their mitochondria to generate ATP, and allowing them the flexibility to use fatty acids or glucose as nutrients to fuel core metabolism. These data provide novel mechanistic insights into how mTOR modulates DC metabolism and cellular longevity following TLR activation and provide an explanation for previous findings that mTOR inhibition enhances the efficacy of DCs in autologous vaccination.

Immunometabolism: Cellular Metabolism Turns Immune Regulator

“…Over the course of 18 h, activated DC sustain elevated glycolysis and inactivate OxPhos (33). This metabolic shift is important in regulating DC-induced T cell responses, in part due to the fact that it impacts upon DC lifespan and thus the duration over which DC can activate T cells (37,38). The metabolism of granulocytes is best characterized for neutrophils, which rely almost entirely on glycolysis and exhibit very low levels of OxPhos (28 -30, 39).…”

“…Certainly, in activated DC, preserving OxPhos results in an increased cellular lifespan (38). Moreover, in macrophages, switching cellular metabolism from glycolysis to oxidative metabolism promotes a shift from short-lived M1 macrophages to longer-lived M2 macrophages (50).…”

Metabolic regulation of immune responses: therapeutic opportunities

“…The absence of mitochondrial ATP synthesis appears to contribute to the short life span of these cells, which is not surprising given the important role for mitochondrial energy metabolism in controlling apoptosis. Certainly, sustaining rates of OxPhos in DCs results in increased DC survival and prolonged DC-induced T cell responses (5). While these cells do not proliferate, glucose is still a key fuel for cellular biosynthesis and is required to meet the biosynthetic demands associated with the production of large quantities of cytokines and other effector molecules (6, 7).…”

“…Arginine depletion within the tumor microenvironment will also affect macrophage function. Arginine has been linked to the inhibition of OxPhos in activated DCs and macrophages as it is a substrate for NO synthase and is required for NO production (5,63,64). NO acts as an inhibitor of mitochondrial complex IV to block OxPhos; inhibition of NO production is predicted to promote regulatory macrophage differentiation and function (25,60,62).…”

The Varieties of Immunological Experience: Of Pathogens, Stress, and Dendritic Cells

“…The interaction between glycolytic reprogramming and the mTOR pathway is evident in the fact that rapamycin extends the life span of TLR-activated DCs by inhibiting the induction of NO production, facilitating oxidative phosphorylation to generate ATP, and thus allowing them the flexibility to use fatty acids or glucose as nutrients to fuel core metabolism (306). These data provide an explanation for previous findings that mTOR inhibition enhances the efficacy of DCs in autologous vaccination (307).…”