Journal of Molecular Biology
Volume 430, Issue 21, 19 October 2018, Pages 3906-3921
Journal home page for Journal of Molecular Biology

Review
How Mitochondrial Metabolism Contributes to Macrophage Phenotype and Functions

https://doi.org/10.1016/j.jmb.2018.07.003Get rights and content

Highlights

  • Innate immune response and metabolic reprogramming are intertwined.

  • Metabolic differences in classical versus alternatively activated macrophages are linked to their function specificities.

  • Mitochondria orchestrate the metabolic and immune adaptations in macrophages

  • Innate immune response promotes changes in mitochondrial supercomplexes assembly and dynamics.

Abstract

Metabolic reprogramming of cells from the innate immune system is one of the most noteworthy topics in immunological research nowadays. Upon infection or tissue damage, innate immune cells, such as macrophages, mobilize various immune and metabolic signals to mount a response best suited to eradicate the threat. Current data indicate that both the immune and metabolic responses are closely interconnected. On account of its peculiar position in regulating both of these processes, the mitochondrion has emerged as a critical organelle that orchestrates the coordinated metabolic and immune adaptations in macrophages. Significant effort is now underway to understand how metabolic features of differentiated macrophages regulate their immune specificities with the eventual goal to manipulate cellular metabolism to control immunity. In this review, we highlight some of the recent work that place cellular and mitochondrial metabolism in a central position in the macrophage differentiation program.

Introduction

The mammalian immune system hangs on two distinct branches that efficiently intertwine to eradicate pathogens, initiate tissue repair, and restore homeostasis [1], [2]. The first branch, termed innate immune system, constitutes the early first layer of immune defense. Upon infection, tissue-invading microorganisms such as bacteria rapidly encounter cells from the innate immune system including professional phagocytes such as neutrophils, macrophages, monocytes or dendritic cells. These cells engulf and destroy invading pathogens and secrete various cytokines and chemokines to mount a specific immune response. When the innate immune system does not sufficiently destroy invading microorganisms, professional cells of the adaptive immune system, which includes T and B lymphocytes, eliminate the pathogens and provide protective immunity. The molecular mechanisms governing activation of immune cells are now well characterized and involve a variety of surface and cytosolic receptors as well as numerous signaling protein adaptors and kinases, which all contribute to the success of the immune response [3], [4]. Recently, scientists studying the innate and adaptive immune systems revisited seminal work from the 60s and 80s [5], [6], and realized that profound rearrangement of immune cell metabolism is associated with activation processes and likely sets the specificities of nascent immune responses [7], [8]. This includes release of metabolites in the micro-environment and metabolite-mediated control of histone modifications or modification of the redox balance [9], [10]. At the core of these events are mitochondria, which are bioenergetic organelles central to many cellular processes [11]. This is particularly interesting for innate immune cells since mitochondria also serve as signaling platforms for various innate immune cell-specific receptors signaling [10], [12]. Because the molecular regulation of cellular metabolism in the adaptive immune system has been extensively reviewed recently [8], [13], we will focus here on recent advances in our understanding of metabolic adaptations and the role of mitochondria in the immune function using macrophages as a paradigm for innate immune cells.

Section snippets

Innate Immunity and Macrophage Polarization

Epithelia constitute bona fide point of entry for a multitude of pathogens including viruses, bacteria, fungi, and parasites. By their spatial repartition, innate immune cells such as macrophages and dendritic cells constitute a first layer of immune defense against most, if not all, microbes by probing their environment in search of signals that indicate microbial invaders or tissue damage. They express a large group of germline-encoded immune receptors (also called pattern-recognition

Mitochondria dynamics in innate immune cells

Mitochondrial dynamics refers to the capacity of individual mitochondrion to fuse or dissociate to form a reticulated or punctuated network, respectively. When fission prevails, mitochondrial fragmentation occurs and the network looks punctuated. In contrast, mitochondria appear elongated if fusion is prevalent. The dynamics between the two states is tightly coupled to metabolic changes including fuel fluctuations, energy demand, starvation, cold exposure, oxidative stress, calcium handling, or

Conclusions and Future Directions

Although tremendous progress has been achieved in the characterization of metabolic adaptations occurring during macrophage activation, many questions remain unanswered. Most of the research is based on the use of purified single ligand for PRRs. While this represents a clear advantage at the time of performing the experiments and increases the reproducibility of the research, it does not fully cover the complexity of microbial encounter and simultaneous engagement of PRRs. Thus, it would be

Acknowledgments

We thank Dr. Linsey Stiles and Dr. Karel Erion for scientific discussion and English editing. J.G. is supported by the IDEX program of the University of Bordeaux (ANR-10-IDEX-03-02) and by a grant from the Bristol-Myers Squibb Foundation for Research in Immuno-Oncology. R.A.-P. is supported by the BBVA Foundation Grant for Researchers and Cultural Creators.

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