A CREB-C/EBPβ cascade induces M2 macrophage-specific gene expression and promotes muscle injury repair
Open accessAbstract
Macrophages play an essential role in the resolution of tissue damage through removal of necrotic cells, thus paving the way for tissue regeneration. Macrophages also directly support the formation of new tissue to replace the injury, through their acquisition of an anti-inflammatory, or M2, phenotype, characterized by a gene expression program that includes IL-10, the IL-13 receptor, and arginase 1. We report that deletion of two CREB-binding sites from the Cebpb promoter abrogates Cebpb induction upon macrophage activation. This blocks the downstream induction of M2-specific Msr1 , Il10 , II13ra , and Arg-1 genes, whereas the inflammatory (M1) genes Il1 , Il6 , Tnfa , and Il12 are not affected. Mice carrying the mutated Cebpb promoter (βΔCre) remove necrotic tissue from injured muscle, but exhibit severe defects in muscle fiber regeneration. Conditional deletion of the Cebpb gene in muscle cells does not affect regeneration, showing that the C/EBPβ cascade leading to muscle repair is muscle-extrinsic. While βΔCre macrophages efficiently infiltrate injured muscle they fail to upregulate Cebpb , leading to decreased Arg-1 expression. CREB-mediated induction of Cebpb expression is therefore required in infiltrating macrophages for upregulation of M2-specific genes and muscle regeneration, providing a direct genetic link between these two processes.
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Regenerative properties of microglia/macrophages following injury to muscle and skin are associated with alternative or deactivation to M2-polarized phenotypes (M2a and M2c, respectively).
“Regenerative properties of microglia/macrophages following injury to muscle6, 7 and skin8 are associated with alternative or deactivation to M2-polarized phenotypes (M2a and M2c, respectively), which secrete anti-inflammatory cytokines/growth factors9.”
From M2 microglia and macrophages drive oligodendrocyte differentiation during CNS remyelination (2013) · cites this paper as [6]
The Discussion (page unavailable) links muscle regeneration to macrophages acquiring an anti-inflammatory M2 phenotype, and the paper reports impaired muscle repair when M2-specific gene expression is disrupted. It does not identify the muscle-associated phenotype specifically as M2a. The skin/M2c portion is attached to a different citation in the citing sentence, so it is not assessed against this source. (LLM, conf=0.85)
Experimental — accuracy not yet measuredSTAT1 and IRF5 are involved in M1 polarization/maintenance; STAT6, IRF4, CREB-C/EBPβ, and PPARγ are involved in M2 polarization/maintenance.
“Specifically, STAT1 and IRF5 have been shown to be involved in polarization and maintenance of an M1 phenotype while STAT6, IRF4, CREB-C/EBPβ, and PPARγ are involved in polarization and maintenance of an M2 phenotype [23–30].”
From Macrophage polarization: an opportunity for improved outcomes in biomaterials and regenerative medicine (2012) · cites this paper as [24]
In a mouse model of necrotic muscle injury, deletion of two binding sites in the CREB-C/EBPβ pathway blocked induction of M2 associated genes (Msr1, IL-10, IL-13ra, Arg-1) without affecting M1 gene expression; these mice showed fibrotic tissue and decreased myofiber size, unlike wild-type mice with full recovery.
“In this study it was shown that the deletion of two of the binding sites in the CREB-C/EBPβ pathway blocked the induction of M2 associated genes (Msr1, IL-10, IL-13ra, and Arg-1), while M1 gene (IL-1, IL-6, IL-12b, TNFα) expression was not affected.”
From Macrophage polarization: an opportunity for improved outcomes in biomaterials and regenerative medicine (2012) · cites this paper as [24]
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- Authors
- Ruffell, D., Mourkioti, F., Gambardella, A., Kirstetter, P., Lopez, R. G., Rosenthal, N., & Nerlov, C.
- Affiliations
- European Molecular Biology Laboratory (IT)
- Corresponding author
- Nerlov, Claus
- ORCID
- Venue
- Proceedings of the National Academy of Sciences
- Publisher
- National Academy of Sciences
- Published
- 2009-10-13
- Volume
- 106
- Issue
- 41
- Pages
- 17475-17480
- ISSN
- 0027-8424 (ISSN-L)
- 1091-6490
- PMC
- PMC2762675
- OpenAlex
- W2167589136
- Cited by
- 626
- References
- 4
- Citations by year
- 2026: 22 · 2025: 44 · 2024: 39 · 2023: 34 · 2022: 41 · 2021: 44 · 2020: 42 · 2019: 33 · 2018: 36 · 2017: 41 · 2016: 43 · 2015: 60 · 2014: 46 · 2013: 40 · 2012: 27
- FWCI
- 8.77
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Proceedings of the National Academy of Sciences (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- European Commission
- Topics
- Life Sciences › Immunology and Microbiology › Immunology › Immune cells in cancer
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Muscle Physiology and Disorders
- Health Sciences › Medicine › Rehabilitation › Wound Healing and Treatments
- Keywords
- C/EBPβ, CREB binding site, M2 macrophages, macrophage polarization, muscle regeneration, muscle injury repair, arginase-1, IL-10, IL-13 receptor, MSR1, macrophage infiltration, tissue regeneration, conditional gene deletion
- MeSH terms
- Animals, B-Lymphocytes, Binding Sites, Bone Marrow Cells, Gene Expression Regulation, Macrophages, Promoter Regions, Genetic, Regeneration, Transcription Factors, Cyclic AMP Response Element-Binding Protein, Muscle, Skeletal, CCAAT-Enhancer-Binding Protein-beta, Mice
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