Gene regulatory network modeling of macrophage differentiation corroborates the continuum hypothesis of polarization states
Open accessAbstract
Macrophages derived from monocyte precursors undergo specific polarization processes which are influenced by the local tissue environment: classically-activated (M1) macrophages, with a pro-inflammatory activity and a role of effector cells in Th1 cellular immune responses, and alternatively-activated (M2) macrophages, with anti-inflammatory functions and involved in immunosuppression and tissue repair. At least three different subsets of M2 macrophages, namely M2a, M2b and M2c, are characterized in the literature based on their eliciting signals. The activation and polarization of macrophages is achieved through many, often intertwined, signaling pathways. To describe the logical relationships among the genes involved in macrophage polarization, we used a computational modeling methodology, namely, logical (Boolean) modeling of gene regulation. We integrated experimental data and knowledge available in the literature to construct a logical network model for the gene regulation driving macrophage polarization to the M1, M2a, M2b and M2c phenotypes. Using the software GINsim and BoolNet we analysed the network dynamics under different conditions and perturbations to understand how they affect cell polarization. Dynamic simulations of the network model, enacting the most relevant biological conditions, showed coherence with the observed behaviour of in vivo macrophages. The model could correctly reproduce the polarization toward the four main phenotypes as well as to several hybrid phenotypes, which are known to be experimentally associated to physiological and pathological conditions. We surmise that shifts among different phenotypes in the model mimic the hypothetical continuum of macrophage polarization, with M1 and M2 being the extremes of an uninterrupted sequence of states. Furthermore, model simulations suggest that anti-inflammatory macrophages are resilient to shift back to the pro-inflammatory phenotype.
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All three M2 subtypes have anti-inflammatory properties, but M2a and M2b are immunoregulatory and mediate the Th-2 response.
“All three subtypes have anti-inflammatory properties, but M2a and M2b macrophages are considered immunoregulatory and are known to mediate the Th-2 response.”
From Superoxide Anion Chemistry—Its Role at the Core of the Innate Immunity (2023) · cites this paper as [198]
M2c cells are immunosuppressive and are involved in extracellular matrix remodelling.
“M2c cells are immunosuppressive and are involved in extracellular matrix ECM remodelling.”
From Superoxide Anion Chemistry—Its Role at the Core of the Innate Immunity (2023) · cites this paper as [198]
M2a and M2c secrete growth factors that promote angiogenesis and tissue regeneration.
“M2a and M2c secrete growth factors that promote the formation of new blood vessels (angiogenesis) and tissue regeneration [198].”
From Superoxide Anion Chemistry—Its Role at the Core of the Innate Immunity (2023) · cites this paper as [198]
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Jak2-Stat5 Interactions Analyzed in Yeast
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Expression and regulation of long noncoding RNAs in TLR4 signaling in mouse macrophages
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Fcγ Receptor Cross-linking Stimulates Cell Proliferation of Macrophages via the ERK Pathway
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Mathematical Modeling of Pro- and Anti-Inflammatory Signaling in Macrophages
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Computational modeling of heterogeneity and function of CD4+ T cells
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Immune System Modelling and Simulation
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Self-citationStatistical ensemble of gene regulatory networks of macrophage differentiation
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Self-citationMacrophages — Masters of Immune Activation, Suppression and Deviation
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FcγRIIb inhibits immune complex-induced VEGF-A production and intranodal lymphangiogenesis
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Dynamics of Cell-Fate Determination and Patterning in the Vascular Bundles of Arabidopsis thaliana
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Self-citation
Flagged first, then by citations
Research works printed but not linked: 1
- Thomas R. D’Ari R. (1990). Biological Feedback. Boca Raton, FL: CRC Press.
Cited by
Sorted by citations
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
- Authors
- Palma, A., Jarrah, A. S., Tieri, P., Cesareni, G., & Castiglione, F.
- Affiliations
- University of Rome Tor Vergata (IT)
- American University of Sharjah (AE)
- National Research Council (IT)
- Corresponding author
- Castiglione, Filippo
- Venue
- Frontiers in Physiology
- Publisher
- Frontiers Media SA
- Published
- 2018-11-27
- Volume
- 9
- Pages
- 1659-1659
- ISSN
- 1664-042X (ISSN-L)
- PMC
- PMC6278720
- OpenAlex
- W2903465911
- Cited by
- 122
- References
- 112
- Citations by year
- 2026: 11 · 2025: 8 · 2024: 8 · 2023: 16 · 2022: 28 · 2021: 22 · 2020: 23 · 2019: 5 · 2018: 1
- FWCI
- 4.54
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Locations
- Frontiers in Physiology (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- IRIS Research product catalog (Sapienza University of Rome) (submittedVersion, cc-by)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Funders
- European Commission (600803)
- Associazione Italiana per la Ricerca sul Cancro (IG-2017, 20322)
- FP7 Ideas: European Research Council (322749)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Gene Regulatory Network Analysis
- Life Sciences › Immunology and Microbiology › Immunology › Immune cells in cancer
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Bioinformatics and Genomic Networks
- Keywords
- macrophage polarization, macrophage differentiation, M1 macrophages, M2 macrophages, continuum hypothesis, logical modeling, network dynamics, Th1 response, tissue repair
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.
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