Macrophage Polarization and Reprogramming in Acute Inflammation: A Redox Perspective
Open accessAbstract
Macrophage polarization refers to the process by which macrophages can produce two distinct functional phenotypes: M1 or M2. The balance between both strongly affects the progression of inflammatory disorders. Here, we review how redox signals regulate macrophage polarization and reprogramming during acute inflammation. In M1, macrophages augment NADPH oxidase isoform 2 (NOX2), inducible nitric oxide synthase (iNOS), synaptotagmin-binding cytoplasmic RNA interacting protein (SYNCRIP), and tumor necrosis factor receptor-associated factor 6 increase oxygen and nitrogen reactive species, which triggers inflammatory response, phagocytosis, and cytotoxicity. In M2, macrophages down-regulate NOX2, iNOS, SYNCRIP, and/or up-regulate arginase and superoxide dismutase type 1, counteract oxidative and nitrosative stress, and favor anti-inflammatory and tissue repair responses. M1 and M2 macrophages exhibit different metabolic profiles, which are tightly regulated by redox mechanisms. Oxidative and nitrosative stress sustain the M1 phenotype by activating glycolysis and lipid biosynthesis, but by inhibiting tricarboxylic acid cycle and oxidative phosphorylation. This metabolic profile is reversed in M2 macrophages because of changes in the redox state. Therefore, new therapies based on redox mechanisms have emerged to treat acute inflammation with positive results, which highlights the relevance of redox signaling as a master regulator of macrophage reprogramming.
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M1 macrophages produce intracellular nitric oxide by iNOS and superoxide anion O2•− and subsequent reactive species, which are cytotoxic to microbial agents and fight infection.
“M1 macrophages produce intracellular nitric oxide •NO by inducible nitric oxide synthase iNOS and superoxide anion O2•− and subsequent reactive species, which are cytotoxic to microbial agents and fight infection [195].”
From Superoxide Anion Chemistry—Its Role at the Core of the Innate Immunity (2023) · cites this paper as [195]
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Coffey, M., Phare, S. M., Luo, M., et al. (2008) · Biochimica et Biophysica Acta (BBA) - Molecular and Cell Biology of Lipids · doi:10.1016/j.bbalip.2008.04.005 · Cited by 15 · see citing works
Bonjoch, L., Gea‐Sorlí, S., & Closa, D. (2015) · Pancreatology · doi:10.1016/j.pan.2015.04.007 · Cited by 14 · see citing works
Glutaredoxin 1 regulates macrophage polarization through mediating glutathionylation of STAT1
Guo, L., Chen, S., Liu, Q., et al. (2020) · Thoracic Cancer · doi:10.1111/1759-7714.13647 · Cited by 14 · see citing works
Li, Y., Yu, W.-H., He, M., et al. (2021) · The Nephron journals/Nephron journals · doi:10.1159/000513268 · Cited by 7 · see citing works
Novel chloroacetamido compound CWR-J02 is an anti-inflammatory glutaredoxin-1 inhibitor
Miller, O. G., Cole, K. S., Emerson, C. C., et al. (2017) · PLoS ONE · doi:10.1371/journal.pone.0187991 · Cited by 6 · see citing works
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Superoxide Anion Chemistry—Its Role at the Core of the Innate Immunity
Andrés, C. M. C., Pérez de la Lastra, J. M., Andrés Juan, C., Plou, F. J., & Pérez-Lebeña, E. (2023) · International Journal of Molecular Sciences · doi:10.3390/ijms24031841 · Cited by 342 · see citing works
Beyond M1/M2: The role of reactive oxygen species in liver fibrosis and immune modulation
Lu, H., Huang, J., Wang, Y.-C., Casals, E., Casals, G., & Zeng, M. (2025) · Redox Biology · doi:10.1016/j.redox.2025.103933 · Cited by 19 · see citing works
Molecular control of PDPNhi macrophage subset induction by ADAP as a host defense in sepsis
Zhang, P., Wang, X., Yang, X., & Liu, H. (2025) · JCI Insight · doi:10.1172/jci.insight.186456 · Cited by 10 · see citing works
- Authors
- Pérez, S., & Rius-Pérez, S.
- Affiliations
- Universitat de València (ES)
- Department of Physiology, Faculty of Pharmacy, University of Valencia, Burjasot, 46100 Valencia, Spain
- Corresponding author
- Pérez, Salvador
- ORCID
- Pérez, Salvador
- Venue
- Antioxidants
- Publisher
- MDPI AG
- Published
- 2022-07-19
- Volume
- 11
- Issue
- 7
- Pages
- 1394
- ISSN
- 2076-3921 (ISSN-L)
- PMC
- PMC9311967
- OpenAlex
- W4285794323
- Cited by
- 312
- References
- 191
- Citations by year
- 2026: 75 · 2025: 118 · 2024: 76 · 2023: 36 · 2022: 7
- FWCI
- 6.25
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- Antioxidants (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Funders
- Generalitat Valenciana, Conselleria d’Educació, Investigació, Cultura I Esport (GV/2021/150)
- Topics
- Life Sciences › Immunology and Microbiology › Immunology › Immune cells in cancer
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Redox biology and oxidative stress
- Life Sciences › Immunology and Microbiology › Immunology › Neutrophil, Myeloperoxidase and Oxidative Mechanisms
- Keywords
- macrophage polarization, M1/M2 macrophages, acute inflammation, redox signaling, oxidative stress, nitrosative stress, NADPH oxidase 2, inducible nitric oxide synthase, SYNCRIP, TRAF6, arginase, superoxide dismutase 1, macrophage metabolism, glycolysis, lipogenesis, TCA cycle, oxidative phosphorylation, anti-inflammatory therapy
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
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