Glycolysis regulates LPS-induced cytokine production in M2 polarized human macrophages.

M1 and M2 macrophages are the key players in innate immunity, and are associated with tissue homeostasis and diseases. Although M2 macrophages are known to depend on fatty acid oxidation (FAO) for their activation, how metabolic pathways affect the production of each cytokine induced by pathogen or bacterial components is unclear. Here, we examined the role of the glycolytic pathway in M2 polarized human macrophages in cytokine production induced by lipopolysaccharide (LPS) stimulation. Human monocytes were isolated from peripheral blood by positive selection for CD14 expression and cultured with macrophage colony-stimulating factor (M-CSF), to obtain M-CSF-induced macrophages (M-MΦ). LPS-induced cytokine production by M-MΦ in the presence or absence of metabolic inhibitors was evaluated. M-MΦ showed a M2 macrophage phenotype with a high IL-10 production level. Glycolytic pathway inhibitors reduced IL-6 production by M-MΦ. Meanwhile, an FAO inhibitor suppressed IL-10 production, while it did not suppress IL-6 production. Interestingly, glycolytic pathway inhibitors downregulated extracellular signal-regulated kinase (ERK) phosphorylation, but FAO inhibitor did not. Nuclear factor kappa B (NF-κB) and the other mitogen-activated protein kinases (MAPKs), p38 and c-jun N-terminal kinase (JNK), were not affected by these metabolic inhibitors. These results suggest that M2 polarized human macrophages use the glycolytic pathway in addition to FAO for cytokine production. Furthermore, ERK may be the key molecule that links metabolic pathways to cytokine production, especially the glycolytic pathway.

Chiba S ，Hisamatsu T ，Suzuki H ，Mori K ，Kitazume MT ，Shimamura K ，Mizuno S ，Nakamoto N ，Matsuoka K ，Naganuma M ，Kanai T ... -  《-》

Aloe vera downregulates LPS-induced inflammatory cytokine production and expression of NLRP3 inflammasome in human macrophages.

Budai MM ，Varga A ，Milesz S ，Tőzsér J ，Benkő S ... -  《-》

TLR2 stimulation impairs anti-inflammatory activity of M2-like macrophages, generating a chimeric M1/M2 phenotype.

Quero L ，Hanser E ，Manigold T ，Tiaden AN ，Kyburz D ... -  《-》

Glycolytic pathway affects differentiation of human monocytes to regulatory macrophages.

Cellular metabolic state and individual metabolites have been reported to regulate the functional phenotype of immune cells. Cytokine production by regulatory and inflammatory macrophages is thought to mainly involve fatty acid oxidation and glycolysis, respectively, which fuel mitochondrial oxidative phosphorylation. However, the association between metabolic pathways and the acquisition of specific macrophage phenotypes remains unclear. This study assessed the relationship between glycolysis and the differentiation of regulatory macrophages. Human monocytes derived from peripheral blood were cultured in vitro in the presence of macrophage colony-stimulating factor to yield regulatory macrophages (M-Mϕs). M-Mϕs had a regulatory macrophage phenotype and produced substantial IL-10 following stimulation with lipopolysaccharide. To analyze the role of glycolysis, glycolysis inhibitors (2-deoxy-d-glucose or dichloroacetate) were added during M-Mϕ differentiation. These cells cultured with glycolysis inhibitors produced significantly lower amounts of IL-10, but produced significantly higher amounts of IL-6 compared to M-Mϕs differentiated without glycolysis inhibitors. Such phenotypic change of M-Mϕs differentiated with glycolysis inhibitors was associated with the alteration of the gene expression pattern related to macrophage differentiation, such as CSF1, MMP9 and VEGFA. M-Mϕs differentiated with glycolysis inhibitors seemed to retain plasticity to become IL-10 producing cells. Furthermore, increased level of pyruvate in culture medium was found to partially reverse the effects of glycolysis inhibitors on cytokine production of M-Mϕs. These results indicate the importance of glycolytic pathway in macrophage differentiation to a regulatory phenotype, and pyruvate may be one of the key metabolites in this process.

Suzuki H ，Hisamatsu T ，Chiba S ，Mori K ，Kitazume MT ，Shimamura K ，Nakamoto N ，Matsuoka K ，Ebinuma H ，Naganuma M ，Kanai T ... -  《-》

Inflammatory responses induced by lipopolysaccharide are amplified in primary human monocytes but suppressed in macrophages by complement protein C5a.

Seow V ，Lim J ，Iyer A ，Suen JY ，Ariffin JK ，Hohenhaus DM ，Sweet MJ ，Fairlie DP ... -  《-》