Macrophages are a heterogeneous population of immune cells playing several and diverse functions in homeostatic and immune responses. The broad spectrum of macrophage functions depends on both heterogeneity and plasticity of these cells, which are highly specialized in sensing the microenvironment and modify their properties accordingly. Although it is clear that macrophage phenotypes are difficult to categorize and should be seen as plastic and adaptable, they can be simplified into two extremes: a pro-inflammatory (M1) and an anti-inflammatory/pro-resolving (M2) profile. Based on this definition, M1 macrophages are able to start and sustain inflammatory responses, secreting pro-inflammatory cytokines, activating endothelial cells, and inducing the recruitment of other immune cells into the inflamed tissue; on the other hand, M2 macrophages promote the resolution of inflammation, phagocytose apoptotic cells, drive collagen deposition, coordinate tissue integrity, and release anti-inflammatory mediators. Dramatic switches in cell metabolism accompany these phenotypic and functional changes of macrophages. In particular, M1 macrophages rely mainly on glycolysis and present two breaks on the TCA cycle that result in accumulation of itaconate (a microbicide compound) and succinate. Excess of succinate leads to Hypoxia Inducible Factor 1α (HIF1α) stabilization that, in turn, activates the transcription of glycolytic genes, thus sustaining the glycolytic metabolism of M1 macrophages. On the contrary, M2 cells are more dependent on oxidative phosphorylation (OXPHOS), their TCA cycle is intact and provides the substrates for the complexes of the electron transport chain (ETC). Moreover, pro- and anti-inflammatory macrophages are characterized by specific pathways that regulate the metabolism of lipids and amino acids and affect their responses. All these metabolic adaptations are functional to support macrophage activities as well as to sustain their polarization in specific contexts. The aim of this review is to discuss recent findings linking macrophage functions and metabolism.

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The Metabolic Signature of Macrophage Responses.

Macrophages and Metabolism in the Tumor Microenvironment

Macrophage Immunometabolism: Where Are We (Going)?

Traditionally cellular respiration or metabolism has been viewed as catabolic and anabolic pathways generating energy and biosynthetic precursors required for growth and general cellular maintenance. However, growing literature provides evidence of a much broader role for metabolic reactions and processes in controlling immunological effector functions. Much of this research into immunometabolism has focused on macrophages, cells that are central in pro- as well as anti-inflammatory responses-responses that in turn are a direct result of metabolic reprogramming. As we learn more about the precise role of metabolic pathways and pathway intermediates in immune function, a novel opportunity to target immunometabolism therapeutically has emerged. Here, we review the current understanding of the regulation of macrophage function through metabolic remodeling.

/pdf/metabolic-modulation-in-macrophage-effector-function-4fyz7qtnv5.pdf

Metabolic Modulation in Macrophage Effector Function.

Metabolic changes in tumor cells and tumor-associated macrophages: A mutual relationship.

Tumor-associated macrophages (TAMs) are major components of the tumor microenvironment. Although a role for TAMs in promoting tumor progression has been revealed, the differentiation mechanisms and intrinsic signals of TAMs regulated by the tumor microenvironment remain unclear. Here we constructed an in vitro TAMs cell model, TES-TAMs, which is from tumor-extract-stimulated bone-marrow-derived macrophages. We performed a comparative proteomics analysis of bone-marrow-derived macrophages and TES-TAMs, which indicated that TES-TAMs possessed characteristic molecular expression of TAMs. Intriguingly, the signal pathways enriched in up-regulated differentially expressed proteins of TAMs demonstrated that glycolysis metabolism reprogramming may play an important role in TAM differentiation. We found that hexokinase-2, a key mediator of aerobic glycolysis, and the downstream proteins PFKL and ENO1 were remarkably increased in both TES-TAMs and primary TAMs from our MMTV-PyMT mice model. This phenomenon was the...

Comprehensive Proteomics Analysis Reveals Metabolic Reprogramming of Tumor-Associated Macrophages Stimulated by the Tumor Microenvironment

Objective To detect the phenotypic conversion of tumor-associated macrophages (TAMs) through analyzing the expression levels of the polarization-related genes. Methods We identified the spontaneous breast cancer mice by genotyping and characterized them into the early stage and the advanced stage groups according to their tumor size. Single cell suspension of the tumor tissues were obtained by mechanical methods and TAMs of different stages were sorted by flow cytometry. We measured the mRNA levels of M1 macrophages-related genes IL-1β, IL-27, IL-6, CD80, CD86 and M2 macrophages-related genes arginase 1 (Arg1), IL-10, interleukin 4 receptor α (IL-4Rα), macrophage mannose receptor 1 (Mrc1), chitinase-like 3 (Chil3/Ym1) by real-time quantitative PCR in order to analyze the phenotypic conversion of TAMs during the tumor progression. Results In the early stage, TAMs expressed high levels of M1-related genes, such as IL-1β, CD80, CD86. On the contrary, TAMs of advanced stage expressed high levels of M2-related genes, including Arg1, IL-10, IL-4Rα as well as IL-6. Conclusion Phenotypic conversion of TAMs is present in tumor progression, and targeting the phenotypes of TAMs may provide potential therapies for breast cancer.

Xiaojie Ren

Papers

Comprehensive Proteomics Analysis Reveals Metabolic Reprogramming of Tumor-Associated Macrophages Stimulated by the Tumor Microenvironment

[Detection and analysis of phenotypes of tumor-associated macrophages in mouse model of spontaneous breast cancer].