Aerobic glycolysis is a metabolic requirement to maintain the M2-like polarization of tumor-associated macrophages.

Macrophages (MO) are versatile cells, assuming distinct functional phenotypes depending on the activating stimulus and the microenvironment. The differential activation of macrophages is supported by profound intracellular metabolic changes, being well accepted that the M1/M(LPS+IFN-γ) phenotype rely on aerobic glycolysis, while M2/M(IL-4) macrophages depend on oxidative metabolism. On the other hand, although tumor-associated macrophages (TAMs) are characterized by their high expression of M2/M(IL-4) markers, is currently unclear whether TAMs present the same oxidative metabolic profile of M2/M(IL-4) cells. Herein, we demonstrate for the first time that despite their high expression of M2/M(IL-4) markers, TAMs show high glycolytic activity, with high lactate secretion similar to the M1/M(LPS+ IFN-γ) phenotype. This activity seems to be essential for the M2 profile of TAMs, since the inhibition of glycolysis, but not the impairment of the oxidative phosphorylation or pentose phosphate pathway, diminished the expression of M2/M(IL-4) markers. These novel data indicate that TAMs, although are usually phenotyped as M2/M(IL-4)-like macrophages, they are metabolically distinct from these cells, being rather similar to M1/M(LPS+IFN-γ) macrophages, depending on the glycolytic metabolism to support their profile and functions.

M de-Brito N ，Duncan-Moretti J ，C da-Costa H ，Saldanha-Gama R ，Paula-Neto HA ，G Dorighello G ，L Simões R ，Barja-Fidalgo C ... -  《-》

Cellular metabolism and macrophage functional polarization.

Zhu L ，Zhao Q ，Yang T ，Ding W ，Zhao Y ... -  《-》

Autocrine IL-10 functions as a rheostat for M1 macrophage glycolytic commitment by tuning nitric oxide production.

Inflammatory maturation of M1 macrophages by proinflammatory stimuli such as toll like receptor ligands results in profound metabolic reprogramming resulting in commitment to aerobic glycolysis as evidenced by repression of mitochondrial oxidative phosphorylation (OXPHOS) and enhanced glucose utilization. In contrast, "alternatively activated" macrophages adopt a metabolic program dominated by fatty acid-fueled OXPHOS. Despite the known importance of these developmental stages on the qualitative aspects of an inflammatory response, relatively little is know regarding the regulation of these metabolic adjustments. Here we provide evidence that the immunosuppressive cytokine IL-10 defines a metabolic regulatory loop. Our data show for the first time that lipopolysaccharide (LPS)-induced glycolytic flux controls IL-10-production via regulation of mammalian target of rapamycin (mTOR) and that autocrine IL-10 in turn regulates macrophage nitric oxide (NO) production. Genetic and pharmacological manipulation of IL-10 and nitric oxide (NO) establish that metabolically regulated autocrine IL-10 controls glycolytic commitment by limiting NO-mediated suppression of OXPHOS. Together these data support a model where autocine IL-10 production is controlled by glycolytic flux in turn regulating glycolytic commitment by preserving OXPHOS via suppression of NO. We propose that this IL-10-driven metabolic rheostat maintains metabolic equilibrium during M1 macrophage differentiation and that perturbation of this regulatory loop, either directly by exogenous cellular sources of IL-10 or indirectly via limitations in glucose availability, skews the cellular metabolic program altering the balance between inflammatory and immunosuppressive phenotypes.

Baseler WA ，Davies LC ，Quigley L ，Ridnour LA ，Weiss JM ，Hussain SP ，Wink DA ，McVicar DW ... -  《Redox Biology》

Fish Macrophages Show Distinct Metabolic Signatures Upon Polarization.

Macrophages play important roles in conditions ranging from host immune defense to tissue regeneration and polarize their functional phenotype accordingly. Next to differences in the use of L-arginine and the production of different cytokines, inflammatory M1 macrophages and anti-inflammatory M2 macrophages are also metabolically distinct. In mammals, M1 macrophages show metabolic reprogramming toward glycolysis, while M2 macrophages rely on oxidative phosphorylation to generate energy. The presence of polarized functional immune phenotypes conserved from mammals to fish led us to hypothesize that a similar metabolic reprogramming in polarized macrophages exists in carp. We studied mitochondrial function of M1 and M2 carp macrophages under basal and stressed conditions to determine oxidative capacity by real-time measurements of oxygen consumption and glycolytic capacity by measuring lactate-based acidification. In M1 macrophages, we found increased nitric oxide production and irg1 expression in addition to altered oxidative phosphorylation and glycolysis. In M2 macrophages, we found increased arginase activity, and both oxidative phosphorylation and glycolysis were similar to control macrophages. These results indicate that M1 and M2 carp macrophages show distinct metabolic signatures and indicate that metabolic reprogramming may occur in carp M1 macrophages. This immunometabolic reprogramming likely supports the inflammatory phenotype of polarized macrophages in teleost fish such as carp, similar to what has been shown in mammals.

Wentzel AS ，Janssen JJE ，de Boer VCJ ，van Veen WG ，Forlenza M ，Wiegertjes GF ... -  《Frontiers in Immunology》

Effect of colorectal cancer-derived extracellular vesicles on the immunophenotype and cytokine secretion profile of monocytes and macrophages.

Popēna I ，Ābols A ，Saulīte L ，Pleiko K ，Zandberga E ，Jēkabsons K ，Endzeliņš E ，Llorente A ，Linē A ，Riekstiņa U ... -  《Cell Communication and Signaling》