The metabolic signature of macrophage responses
Open accessAbstract
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 M2 phenotype can be subdivided into M2a, M2b and M2c based on specific functions.
“This phenotype can be further subdivided into M2a, M2b and M2c, based on their specific functions.”
From Superoxide Anion Chemistry—Its Role at the Core of the Innate Immunity (2023) · cites this paper as [197]
Secretion of IL-10 is the hallmark of M2 macrophages, along with arginase-1 and more organic compounds.
“The secretion of the inflammation-inhibiting cytokine IL-10 is the hallmark of M2 macrophages, arginase-1 and more organic compounds [197].”
From Superoxide Anion Chemistry—Its Role at the Core of the Innate Immunity (2023) · cites this paper as [197]
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- Authors
- Viola, A., Munari, F., Sánchez-Rodríguez, R., Scolaro, T., & Castegna, A.
- Affiliations
- University of Padua (IT)
- Institute of Biomembranes, Bioenergetics and Molecular Biotechnologies (IT)
- Corresponding author
- Viola, Antonella
- Castegna, Alessandra
- Venue
- Frontiers in Immunology
- Publisher
- Frontiers Media SA
- Published
- 2019-07-03
- Volume
- 10
- Pages
- 1462-1462
- ISSN
- 1664-3224 (ISSN-L)
- PMC
- PMC6618143
- OpenAlex
- W2955084980
- Cited by
- 2,021
- References
- 186
- Citations by year
- 2026: 282 · 2025: 339 · 2024: 367 · 2023: 332 · 2022: 326 · 2021: 239 · 2020: 132 · 2019: 4
- FWCI
- 15.16
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- Frontiers in Immunology (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- CINECA IRIS Institutional Research Information System (University of Bari Aldo Moro) (submittedVersion, cc-by)
- Padua Research Archive (University of Padova) (submittedVersion, cc-by-nc)
- Funders
- FP7 Ideas: European Research Council (322823)
- Topics
- Life Sciences › Immunology and Microbiology › Immunology › Immune cells in cancer
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Hypoxia, and Metabolism
- Life Sciences › Immunology and Microbiology › Immunology › Phagocytosis and Immune Regulation
- Keywords
- macrophage metabolism, macrophage polarization, M1 macrophages, M2 macrophages, glycolysis, oxidative phosphorylation, itaconate, succinic acid, HIF-1α, TCA cycle, lipid metabolism, amino acid metabolism, inflammation resolution, inflammatory cytokines
- MeSH terms
- Citric Acid Cycle, Glycolysis, Humans, Inflammation, Macrophage Activation, Macrophages, Oxidation-Reduction, Oxidative Phosphorylation
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