Glucose Controls Morphodynamics of LPS-Stimulated Macrophages

Abstract

Macrophages constantly undergo morphological changes when quiescently surveying the tissue milieu for signs of microbial infection or damage, or after activation when they are phagocytosing cellular debris or foreign material. These morphofunctional alterations require active actin cytoskeleton remodeling and metabolic adaptation. Here we analyzed RAW 264.7 and Maf-DKO macrophages as models to study whether there is a specific association between aspects of carbohydrate metabolism and actin-based processes in LPS-stimulated macrophages. We demonstrate that the capacity to undergo LPS-induced cell shape changes and to phagocytose complement-opsonized zymosan (COZ) particles does not depend on oxidative phosphorylation activity but is fueled by glycolysis. Different macrophage activities like spreading, formation of cell protrusions, as well as phagocytosis of COZ, were thereby strongly reliant on the presence of low levels of extracellular glucose. Since global ATP production was not affected by rewiring of glucose catabolism and inhibition of glycolysis by 2-deoxy-D-glucose and glucose deprivation had differential effects, our observations suggest a non-metabolic role for glucose in actin cytoskeletal remodeling in macrophages, e.g. via posttranslational modification of receptors or signaling molecules, or other effects on the machinery that drives actin cytoskeletal changes. Our findings impute a decisive role for the nutrient state of the tissue microenvironment in macrophage morphodynamics.

Aldose reductase (AKR1B) deficiency promotes phagocytosis in bone marrow derived mouse macrophages

“…These findings are consistent with previous observations showing that upon inflammatory challenge, such as stimulation with the TLR4 agonist LPS, macrophages upregulate their glycolytic activity, which is required not only to fuel increased cytokine production, but also phagocytosis [30]. These studies have shown that different macrophage activities, like spreading, formation of cell protrusions, as a cell phagocytosis of complement-opsonized particles rely on extracellular glucose and are fueled by glycolysis, not oxidative phosphorylation [30]. Hence, the increase phagocytosis in AR-null macrophages is consistent with increased glycolysis and elevated levels of ATP in these cells.…”

Enzyme-free monitoring of glucose utilization in stimulated macrophages using carbon nanotube-decorated electrochemical sensor

“…9). A recent report has demonstrated that LPS-stimulated macrophages exhibit down-regulation of ATP synthesis from fatty acid oxidation and hence is heavily dependent on the glycolytic pathway and not the oxidative phosphorylation to meet the energy demands associated with the cytoskeletal remodeling (Venter et al 2014). Our data support this mechanism as we observe a distinct twofold increase in the glucose utilization by macrophages stimulated with LPS.…”

Myo19 is an outer mitochondrial membrane motor and effector of starvation-induced filopodia

“…S1C). Supplementation of the starvation medium with glucose completely prevented both protrusions and foci formation, indicating that it is a response to glucose starvation rather than other nutrients (Venter et al, 2014) (Fig. 1C).…”