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अमूर्त

Glycolytic Metabolism is Differentially Coupled to Proliferative Potential and Morphodynamic Capacity in RAW 264.7 and Mafb/C-Maf Deficient Macrophage Lineages

Gerda Venter, Mietske Wijers, Frank TJJ Oerlemans, Ganesh Manjeri, Jack AM Fransen and Bé Wieringa

Background: Macrophages are highly specialized immune cells of different developmental origin, which occur in a continuum of diverse functional states in almost all tissues. In order to fulfil their complex role in tissue homeostasis and defence against pathogens they must be able to live with heterogeneous extrinsic nutrient conditions in tissue niches and handle variation in intrinsic metabolic demand that is determined by differentiation state, functional specialization and immune challenge. The purpose of the present study was to gain more insight in how metabolic specialization and versatility in fate and immune effector function of macrophages are coupled.
Methods: In vitro phenotypic characteristics of two macrophage cell lineages of profoundly different developmental origin and polarization capacity, RAW 264.7 and Maf-DKO cells, were analysed. By use of biochemical and cell biological approaches and scanning electron microscopy, we studied the metabolic profiles of these two types of macrophages in relation to proliferative capacity, morphological appearance of cell surface and cell shape, and phagocytic activity as index of morphodynamic potential.
Results: Comparison of gross features of carbohydrate metabolism, including levels of glycolytic enzymes Hexokinase (HK), Pyruvate Kinase (PK-M2), lactate dehydrogenase and nicotinamide phosphoribosyltransferase (Nampt), glucose and oxygen consumption and lactate production rates, and intracellular concentrations and redox ratios of NAD(P)(H) demonstrated that RAW 264.7 and Maf-DKO cells are conspicuously similar in that they both rely heavily on the use of glycolysis. In this respect they share many characteristics with primary macrophages. Strikingly, this uniform metabolic signature does not translate in behavioral-functional similarities as RAW 264.7 cells have a significantly higher proliferation rate, whereas Maf-DKO cells appear to be morphodynamically more active, form significantly more surface membrane protrusions and phagocytose complement opsonized particles much more efficiently.
Conclusion: We conclude that the global rate of glycolysis in intermediary carbohydrate metabolism is similar for the two cell lineages, but that they can make differential use of this important pathway, either to fuel high morphodynamic activity in Maf-DKO cells, or for the sustenance of cell growth in fast proliferating RAW 264.7 cells. Our findings are in keeping with the idea that macrophages may uniformly prefer use of the rapid response time of glycolysis because this pathway provides them with the ability to meet any possible short-timescale energy demand required for immune function.