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.
Highlights
Macrophages are present in all tissues where they provide a first line of defense against pathogens and help to maintain steady-state tissue homeostasis by eliminating foreign matter and apoptotic cells via phagocytosis [1,2]
In order to find a range of conditions wherein the metabolic state of RAW 264.7 macrophages can be manipulated without compromising cell proliferation and viability, we monitored cells for a period of at least 24 hours in the presence of the complex V oxidative phosphorylation (OXPHOS) inhibitor oligomycin, the competitive glycolysis inhibitor 2-deoxyD-glucose (2-DG), or in the absence of glucose
Increased morphodynamic activity, facilitated by rearrangement of the actin cytoskeleton, is a cellular response characteristic to LPS-stimulated macrophages. This dynamic actin remodeling is essential to macrophage function and considered to be an energy draining process
Summary
Macrophages are present in all tissues where they provide a first line of defense against pathogens and help to maintain steady-state tissue homeostasis by eliminating foreign matter and apoptotic cells via phagocytosis [1,2]. To exert these functions they migrate and constantly survey their immediate environment for signs of tissue damage or presence of invading organisms [1]. M2 macrophages, on the other hand, do not undergo such extensive metabolic change but have a metabolic profile comparable to that of unstimulated cells, with higher TCA-cycle and oxidative activity [5,8]. Tannahill et al [9] have demonstrated that LPS stimulation of macrophages causes an increase in the intracellular TCA-cycle intermediate succinate, which stabilizes M1-associated HIF-1a and thereby regulates the expression of the pro-inflammatory cytokine IL-1b
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