Mitochondrial dysfunction prevents repolarization of inflammatory macrophages
Open accessAbstract
Macrophages are innate immune cells that adopt diverse activation states in response to their microenvironment. Editing macrophage activation to dampen inflammatory diseases by promoting the repolarization of inflammatory (M1) macrophages to anti-inflammatory (M2) macrophages is of high interest. Here, we find that mouse and human M1 macrophages fail to convert into M2 cells upon IL-4 exposure in vitro and in vivo. In sharp contrast, M2 macrophages are more plastic and readily repolarized into an inflammatory M1 state. We identify M1-associated inhibition of mitochondrial oxidative phosphorylation as the factor responsible for preventing M1→M2 repolarization. Inhibiting nitric oxide production, a key effector molecule in M1 cells, dampens the decline in mitochondrial function to improve metabolic and phenotypic reprogramming to M2 macrophages. Thus, inflammatory macrophage activation blunts oxidative phosphorylation, thereby preventing repolarization. Therapeutically restoring mitochondrial function might be useful to improve the reprogramming of inflammatory macrophages into anti-inflammatory cells to control disease.
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iNOS is an important metabolic regulator of the immune response because NO inhibits OXPHOS and oxidative metabolism, thus promoting the glycolytic and proinflammatory phenotype.
“iNOS is an important metabolic regulator of the immune response because NO inhibits OXPHOS and oxidative metabolism, thus promoting the glycolytic and proinflammatory phenotype (169, 170).”
From Metabolic Flexibility as an Adaptation to Energy Resources and Requirements in Health and Disease (2018) · cites this paper as [170]
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- Authors
- Van den Bossche, J., Baardman, J., Otto, N. A., van der Velden, S., Neele, A. E., van den Berg, S. M., Luque-Martin, R., Chen, H.-J., Boshuizen, M. C. S., Ahmed, M., Hoeksema, M. A., de Vos, A. F., & de Winther, M. P. J.
- Affiliations
- Amsterdam UMC Location University of Amsterdam (NL)
- ORCID
- Venue
- Cell Reports
- Publisher
- Elsevier BV
- Published
- 2016-10
- Volume
- 17
- Issue
- 3
- Pages
- 684-696
- ISSN
- 2211-1247 (ISSN-L)
- OpenAlex
- W2530726117
- Cited by
- 1,027
- References
- 52
- Citations by year
- 2026: 126 · 2025: 155 · 2024: 138 · 2023: 123 · 2022: 116 · 2021: 117 · 2020: 91 · 2019: 72 · 2018: 55 · 2017: 32 · 2016: 2
- FWCI
- 32.55
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- Cell Reports (publishedVersion, cc-by-nc-nd)
- PubMed (publishedVersion)
- Pure Amsterdam UMC (publishedVersion, other-oa)
- Data Archiving and Networked Services (DANS) (submittedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Open access LMU (Ludwid Maxmilian's Universitat Munchen) (submittedVersion)
- Topics
- Life Sciences › Immunology and Microbiology › Immunology › Immune cells in cancer
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Mitochondrial Function and Pathology
- Life Sciences › Immunology and Microbiology › Immunology › Phagocytosis and Immune Regulation
- Keywords
- macrophage polarization, mitochondrial dysfunction, oxidative phosphorylation, IL-4, nitric oxide, macrophage metabolic reprogramming, anti-inflammatory macrophages, inflammatory macrophages, macrophage activation
- MeSH terms
- Animals, Glucose, Humans, Inflammation, Interferon-gamma, Lipopolysaccharides, Macrophages, Mice, Inbred C57BL, Mitochondria, Nitric Oxide, Oxidation-Reduction, Oxidative Phosphorylation, Phenotype, Interleukin-4, Cell Polarity, Cell Respiration, Nitric Oxide Synthase Type II
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