Classical Activation of Macrophages Leads to Lipid Droplet Formation Without de novo Fatty Acid Synthesis.

Mauricio Rosas-Ballina,Alexander Schmidt,Dirk Bumann,Xue Li Guan

doi:10.3389/fimmu.2020.00131

Mauricio Rosas-Ballina, Alexander Schmidt + Show 2 more

Open Access

https://doi.org/10.3389/fimmu.2020.00131

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Abstract

Altered lipid metabolism in macrophages is associated with various important inflammatory conditions. Although lipid metabolism is an important target for therapeutic intervention, the metabolic requirement involved in lipid accumulation during pro-inflammatory activation of macrophages remains incompletely characterized. We show here that macrophage activation with IFNγ results in increased aerobic glycolysis, iNOS-dependent inhibition of respiration, and accumulation of triacylglycerol. Surprisingly, metabolite tracing with 13C-labeled glucose revealed that the glucose contributed to the glycerol groups in triacylglycerol (TAG), rather than to de novo synthesis of fatty acids. This is in stark contrast to the otherwise similar metabolism of cancer cells, and previous results obtained in activated macrophages and dendritic cells. Our results establish a novel metabolic pathway whereby glucose provides glycerol to the headgroup of TAG during classical macrophage activation.

Highlights

Activation of macrophages with pro-inflammatory stimuli, known as classical M1 activation, induces a profound shift in energetic metabolism characterized by aerobic glycolysis and decreased mitochondrial substrate oxidation [1, 2]
In order to study the metabolic basis of lipid droplet accumulation, we used IFNγ to activate MafB/c-Maf double deficient (Maf-DKO) primary mouse macrophages. These cells are a bona fide alternative to other macrophage sources such as RAW cells as they are not transformed cells with distorted metabolism typical of cancer cells; maintain a differentiated macrophage phenotype when expanded in culture; and functionally integrate into tissues without causing tumors when transplanted into mice [20, 21]
Inspired by lipid metabolism of cancer cells, the current model of classical M1 activation of macrophages assumes a switch from fatty acid degradation to de novo fatty acid synthesis

Summary

Introduction

Activation of macrophages with pro-inflammatory stimuli, known as classical M1 activation, induces a profound shift in energetic metabolism characterized by aerobic glycolysis and decreased mitochondrial substrate oxidation [1, 2] Lipid accumulation is another salient metabolic feature of phagocyte activation during infection and sterile inflammation [3, 4]. Tracing studies of radiolabeled substrate incorporation into total cellular lipids suggest that de novo fatty acid synthesis from glucose contributes to lipid accumulation in macrophages in murine models of sterile inflammation [15, 16], and in classically-activated macrophages and dendritic cells in vitro [11, 16, 17]. The question remains as to whether lipids accumulating during classical macrophage activation originate from de novo fatty acid synthesis or from an exogenous source of lipid

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