Control of macrophage metabolism and activation by mTOR and Akt signaling

doi:10.1016/j.smim.2015.08.001

Seminars in Immunology

Volume 27, Issue 4, August 2015, Pages 286-296

https://doi.org/10.1016/j.smim.2015.08.001 Get rights and content

Highlights

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The diverse functions of macrophages in various physiological and pathophysiological contexts are likely to be supported by distinct metabolic programs.
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Macrophage polarizing signals induce metabolic shifts that accommodate acquisition and execution of effector activities.
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mTORC1 and Akt are major metabolic nodes that are targeted by macrophage polarizing signals to coordinate such metabolic shifts.
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Perturbations in mTORC1 and Akt signaling alter macrophage metabolism and activation.
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Modulation of macrophage metabolism can be explored in many disease contexts, including intracellular bacterial infection, sepsis, inflammatory bowel disease, and cancer.

Abstract

Macrophages are pleiotropic cells that assume a variety of functions depending on their tissue of residence and tissue state. They maintain homeostasis as well as coordinate responses to stresses such as infection and metabolic challenge. The ability of macrophages to acquire diverse, context-dependent activities requires their activation (or polarization) to distinct functional states. While macrophage activation is well understood at the level of signal transduction and transcriptional regulation, the metabolic underpinnings are poorly understood. Importantly, emerging studies indicate that metabolic shifts play a pivotal role in control of macrophage activation and acquisition of context-dependent effector activities. The signals that drive macrophage activation impinge on metabolic pathways, allowing for coordinate control of macrophage activation and metabolism. Here we discuss how mTOR and Akt, major metabolic regulators and targets of such activation signals, control macrophage metabolism and activation. Dysregulated macrophage activities contribute to many diseases, including infectious, inflammatory, and metabolic diseases and cancer, thus a better understanding of metabolic control of macrophage activation could pave the way to the development of new therapeutic strategies.

Graphical abstract

Introduction

Here we review the role of mTOR and Akt in control of macrophage activation and metabolism. We begin with an overview of mTOR and Akt signaling, followed by a discussion of their roles in macrophage activation as revealed by genetic models in which their activities are perturbed. The metabolic underpinnings of their control of macrophage activation are beginning to be unraveled and is a new and exciting area of research in the field, thus in the last sections, we discuss metabolic control of macrophage activation, and the potential role of the mTOR and Akt signaling in this process.

Section snippets

Overview of mTOR and Akt signaling

The serine threonine kinase mTOR is a key regulator of cellular metabolism that is conserved from yeast to man [1], [2]. In mammals, mTOR exists in two complexes, mTORC1 and mTORC2 (Fig. 1). Other subunits are unique to and define the two complexes, such as Raptor and Rictor in mTORC1 and mTORC2, respectively, and serve to regulate complex stability, activation, and/or activity. mTORC1 couples nutrient availability to major anabolic processes (Fig. 1). In growing/proliferating cells, mTORC1

Activation of mTOR and Akt by macrophage polarizing signals

In contrast, the role of mTOR and Akt signaling in macrophages is much less well-understood. Importantly, emerging studies indicate that macrophage activities require the support of metabolic processes (see below). This suggests that polarizing signals that trigger macrophage activation should also induce metabolic shifts that support the acquisition and execution of relevant effector activities. Consistent with this idea, recent studies show that macrophage polarizing signals regulate mTOR and

Control of macrophage activation by mTOR and Akt signaling

In the next sections, we review studies indicating that Akt and mTOR play key roles in macrophage activation. Most studies to date have focused on how the mTORC1 and Akt pathways control either canonical signaling (e.g. JNK, NF-kB) or metabolic processes (e.g. HIF1α, glycolysis), thus we will discuss these topics separately, but future studies are expected to illuminate how control of the two processes are integrated.

Many studies have implicated a role for Akt in macrophage activation. Here we

Overview of macrophage activation and metabolism

As alluded to above, macrophages are pleiotropic cells that assume diverse functions depending on the context. M1 macrophages upregulate pro-inflammatory and antimicrobial activities, while M2 macrophages coordinate tissue repair and Type 2 immunity. Tissue-resident macrophages mediate tolerance to the gut microflora, insulin sensitivity in white adipose tissue, and thermogenesis in brown adipose tissue [3], [4]. Emerging studies indicate that cellular metabolism and function are intricately

Metabolic control of macrophage activation

Here we discuss examples from recent studies indicating how metabolic shifts and metabolic reprogramming sustain macrophage activation. Because this topic has been comprehensively reviewed [38], [39], [40], we focus on the literature most relevant to mTORC1 and Akt. Diagrams of major metabolic pathways discussed in the text (Fig. 3), as well metabolic control of M1 and M2 activation (Fig. 4), are included for the reader's reference.

In M1 macrophages, LPS stimulation triggers a rapid increase in

Established and likely nodes of metabolic control by mTOR and Akt

Little is known regarding control of macrophage metabolism by mTORC1 and Akt. Here we review their major effector activities in tumor cells and proliferating cells, before discussing established as well as potential nodes of mTORC1- and Akt-mediated control of macrophage metabolism (Fig. 4, Fig. 5).

As mentioned above, mTORC1 promotes the synthesis of proteins, lipids, and nucleotides in growing and proliferating cells [1] (Fig. 1). Its control of protein synthesis is mediated by 4EBP and S6K,

Concluding remarks and future directions

As highlighted by the discussion above, mTORC1 and Akt (and metabolic processes more generally) can exert context-dependent effects in regulation of macrophage activation. M1 and M2 macrophages both increase glutamine utilization, but the metabolite is channeled into different metabolic pathways to support either HIF1α stabilization and IL-1β production or N-glycosylation of cell surface receptors. Likewise, mTORC1-dependent increases in lipid synthesis may support production of lipid mediators

Acknowledgements

The authors are supported by NIH grant R01AI102964 (to T.H.) and Ford Foundation Dissertation Fellowship (to A.C.).

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ReviewControl of macrophage metabolism and activation by mTOR and Akt signaling

Highlights

Abstract

Graphical abstract

Introduction

Section snippets

Overview of mTOR and Akt signaling

Activation of mTOR and Akt by macrophage polarizing signals

Control of macrophage activation by mTOR and Akt signaling

Overview of macrophage activation and metabolism

Metabolic control of macrophage activation

Established and likely nodes of metabolic control by mTOR and Akt

Concluding remarks and future directions

Acknowledgements

Cell

Cell

Trends Immunol.

Blood

Trends Endocrinol. Metabol.: TEM

Immunity

Immunity

J. Biol. Chem.

Cell Metabol.

Cell Metabol.

Cell

Cell

Cell Metabol.

Semin. Cancer Biol.

Cell Metabol.

Cell Metabol.

Blood

Immunity

Blood

Cell Metabol.

J. Biol. Chem.

Curr. Biol.: CB

Trends Immunol.

Immunity

Cell Host Microbe

Cell Host Microbe

Cell Host Microbe

J. Controlled Release: Off. J. Controlled Release Soc.

Signal integration by mTORC1 coordinates nutrient input with biosynthetic output

Nat. Cell Biol.

Protective and pathogenic functions of macrophage subsets

Nat. Rev. Immunol.

Tissue-resident macrophages

Nat. Immunol.

The TSC-mTOR pathway regulates macrophage polarization

Nat. Commun.

Interleukin-4- and interleukin-13-mediated alternatively activated macrophages: roles in homeostasis and disease

Ann. Rev. Immunol.

Review
Control of macrophage metabolism and activation by mTOR and Akt signaling